ODA BULTUM UNIVERSITY

COLLEGE OF NATURAL AND COMPUTATIONAL

SCIENCE

CHEMISTRY DEPARTMENT

Handout of Organic Chemistry II (Chem3042)

COMPILED BY GEDEFA DINSA ([Link]. in Organic Chemistry)

Chiro, Ethiopia

February, 2023

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 Introduction
What is organic chemistry and why should you learn it?
The answers to these questions are all around you. Every living organism is made up of organic
chemicals. The proteins that make up hair, skin, and muscle; the DNA that controls your genetic
inheritance; the foods you nourish; and the drugs that cure you are all organic chemicals. Anyone
interested in life and living things, and wishing to be a part of the remarkable advances in medicine and
life sciences, must first understand organic chemistry. For example, look at the following drawings,
which show the chemical structures of some molecules whose names you might be familiar with.
Although the drawings may seem incomprehensible at this point, don't worry. Soon they will make
perfect sense, and soon you'll be drawing similar structures for any substance you're interested in.

Scheme: structure of some organic compounds

Organic chemistry and you
You are already a highly skilled organic chemist. As you read these words, your eyes use an organic
compound (retinal) to convert visible light into nerve impulses. When you picked up something, your

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muscles performed chemical reactions with sugar to give you the energy you needed. As you
understand, gaps between your brain cells are bridged by simple organic molecules (neurotransmitter
amines) to allow nerve impulses to travel through your brain. And you did all this without consciously
thinking about it. You don't yet understand these processes in your mind as well as you can do them in
your brain and body. You are not alone there. Organic chemistry began as a tentative attempt to
understand the chemistry of life. It has become a trusted basis for global activities that feed, clothe and
heal millions of people without even realizing the role chemistry plays in their lives. Chemists work
with physicists and mathematicians to understand how molecules behave, and with biologists to
understand how interactions between molecules underlie all life. The enlightenment brought by
chemistry in the 20th century was tantamount to a revolution in our understanding of the molecular
world, but in these early decades of the 21st century the revolution is far from complete.
Like all sciences, chemistry holds a unique place in our pattern of understanding the universe. It's the
science of molecules. But organic chemistry is more. It literally creates itself as it grows. Of course, we
need to study molecules of natures, because they are interested in themselves and their functions are
important to our lives. Organic chemistry has always been able to elucidate the mechanisms of life by
creating new molecules that provide information unavailable from the molecules actually present in
living things.
This creation of new molecules has given us new materials like plastics to make things, new dyes to
dye our clothes, new perfumes to wear, and new medicines to cure diseases. Some people think that
some of these activities are unnatural and their products are dangerous or unhealthy.
But these new molecules are being constructed by humans from other molecules that occur naturally on
Earth, using the abilities inherent in our natural brains.
Organic compounds
Organic chemistry began as the chemistry of life when it was thought to be distinct from laboratory
chemistry. Then it became the chemistry of carbon compounds, particularly those found in coal. It is
the chemistry of the compounds formed from carbon and other elements found in living things, in the
products of living things, and wherever carbon is found. The most common organic compounds are
those found in living things and those formed from dead things over millions of years. The organic
compounds known from nature used to be the essential oils that can be distilled from plants and the
alkaloids that can be extracted with acid from crushed plants. Menthol is a famous example of an

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aromatic compound made from spearmint essential oil and cis-jasmone, an example of a perfume
distilled from jasmine flowers.
Natural products have long been used to cure disease, and in the 16th century one thing became
famous: quinine was extracted from the bark of the South American cinchona tree and used to treat
fevers, especially malaria. The Jesuits who did this work (the remedy was known as Jesuit bark) of
course didn't know what the structure of quinine was, but now we do. In addition, quinine's molecular
structure has inspired the design of modern drug molecules that treat malaria much more effectively
than quinine itself. The main reservoir of chemicals available to 19th-century chemists was carbon. The
distillation of coal into gas for kindling and heating (principally hydrogen and carbon monoxide) also
yielded a brown tar rich in aromatic compounds such as benzene, pyridine, phenol, aniline and
thiophene.
Historical development of organic chemistry
The foundations of organic chemistry date back to the mid-17th century when chemistry evolved from
an alchemist’s art to a modern science. Little was known about the chemistry at the time, and the
behaviour of organic substances isolated from plants and animals appeared to differ from that of
inorganic substances found in minerals. Organic compounds were generally low-melting solids and
were typically more difficult to isolate, purify, and work with than high-melting inorganic compounds.
For many chemists, the simplest explanation for the different behaviour between organic and inorganic
compounds was that organic compounds contained a special “vital force” due to their origin in living
sources. Because of this vital force, chemists believed that organic compounds could not exist, just as
inorganic compounds could be made and manipulated in the laboratory.
However, this vitalism theory received a serious blow as early as 1816, when Michel Chevreul
discovered that soap made by reacting alkali with animal fat could be separated into several pure
organic compounds, which he called fatty acids. For the first time an organic substance (fat) was
transformed into others (fatty acids plus glycerin) without the influence of an external vital force.

Little more than a decade later, the vitalistic theory suffered still further when Friedrich Wöhler
discovered in 1828 that it was possible to convert the “inorganic” salt ammonium cyanate into the
“organic” substance urea, which had previously been found in human urine.
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By the mid-1800s, the weight of evidence was clearly against the vitalistic theory and it was clear that
there was no fundamental difference between organic and inorganic compounds. The same
fundamental principles explain the behaviours of all substances, regardless of origin or complexity.
The only distinguishing characteristic of organic chemicals is that all contain the element carbon.
Organic chemistry, then, is the study of carbon compounds.

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 1. The Chemistry of Aromatic Compounds
In the early days of organic chemistry, the word “aromatic” was used to describe aromatically scented
substances such as benzaldehyde (from cherries, peaches, and almonds), toluene (from tolu balsam),
and benzene (from coal distillate). However, it soon turned out that the substances known as aromatics
differed in their chemical behaviour from most other organic compounds. Aromatic compounds are
chemical compounds that consist of conjugated planar ring systems accompanied by delocalized pi-
electron clouds in place of individual alternating double and single bonds, and they exhibit special
stability due to resonance delocalization of π-electrons. They are also called aromatics or arenes. The
best examples are toluene and benzene. The majority of aromatic compounds in nature, therefore, are
produced by plants and micro-organisms, and animals are dependent upon plants for many aromatic
compounds either directly or indirectly.
1.1. Aromaticity
In 1931, German chemist and physicist Sir Erich Hückel proposed a theory to help determine if a
planar ring molecule would have aromatic properties. His rule states that if a cyclic, planar molecule
has 4n+2π electrons, it is considered aromatic. This rule would come to be known as Hückel's Rule.
The Criteria for Aromaticity—Hückel’s Rule
Four structural criteria must be satisfied for a compound to be aromatic.
1. A molecule must be cyclic. To be aromatic, each p orbital must overlap with p orbitals on
adjacent atoms.
2. A molecule must be planar. All adjacent p orbitals must be aligned so that the  electron
density can be delocalized. Since cyclooctatetraene is non-planar, it is not aromatic, and it
undergoes addition reactions just like those of other alkenes.

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 3. A molecule must be completely conjugated. Aromatic compounds must have a p orbital on
every atom.

4. A molecule must satisfy Hückel’s rule, and contain a particular number of  electrons.
Hückel's rule:

Benzene is aromatic and especially stable because it contains 6  electrons. Cyclobutadiene is

antiaromatic and especially unstable because it contains 4  electrons.

Considering aromaticity, a compound can be classified in one of three ways:

1. Aromatic—A cyclic, planar, completely conjugated compound with 4n + 2  electrons. It is
less reactive and highly stable.
2. Antiaromatic—A cyclic, planar, completely conjugated compound with 4n  electrons. It is
highly reactive and unstable.
3. Not aromatic (non-aromatic)—a compound that lacks one (or more) of the following
requirements for aromaticity: being cyclic, planar, and completely conjugated. Its less reactive
and unstable.
Thus systems with 2, 6, 10 and 14 …π electrons are aromatic. Systems with 4, 8 and 12 … π electrons
are antiaromatic. An aromatic compound is more stable than an analogous cyclic compound with

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localized electrons. In contrast, an antiaromatic compound is less stable than an analogous cyclic
compound with localized electrons. Aromaticity is characterized by stability, whereas antiaromaticity
is characterized by instability.
Order of stability is Aromatic compound >cyclic compound with localized electrons
>antiaromatic.

Examples of Aromatic Rings

Which of these is aromatic?

CH2

A B

Answer =A) is aromatic. Count the number of pi bonds in the outer ring. A has 5 which means 10 pi
electrons, 4(2) +2=10. While B has 6 pi bonds and 12 pi electrons, 4(3) =12. Doesn’t meet the Huckel
rule requirements for aromaticity.

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Is this compound aromatic or antiaromatic?

Answer =Antiaromatic – cyclic, planar, conjugated, but does not meet Huckel’s rule. 4 double bonds
and 2 triple bonds so 4(2) + 2(4) =16 pi electron’s.
Indicate which of the following compounds are aromatic, not aromatic and antiaromatic?

B
A

C is aromatic 4(3) +2=14

A is antiaromatic 4(2) =8
The Annulenes:
 Annulenes are monocyclic compounds with alternating double and single bonds
 Annulenes are named using a number in brackets that indicates the ring size
Ex. Benzene is [6] annulene and cyclooctatetraene is [8] annulene
An annulene is aromatic if it has 4n+2πelectrons and a planar carbon skeleton

1.2. Properties of Benzene and its Derivatives

 Benzene is an aromatic compound because the six π-electrons are delocalized over the planar 6-
membered ring.
 The delocalization of electrons results in an increase in stability, and benzene is therefore less
reactive than alkenes or alkynes.
 Benzene generally undergoes electrophilic substitution reactions, in which a hydrogen atom is
substituted for an electrophile.

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  Electron-donating substituents (on the benzene ring) (EDG) make the ring more reactive
towards further electrophilic substitution and direct the electrophile to the ortho-/para-
positions.
In contrast, electron-withdrawing substituents (on the benzene ring) (EWG) make the ring less reactive
towards further electrophilic substitution and direct the electrophile to the meta- position
Benzene is much more stable than would be expected based on calculations for
―cyclohexatriene.

1.3. Heterocyclic Aromatic Compounds

A compound does not have to be a hydrocarbon to be aromatic. Many heterocyclic compounds are
aromatic
 A heterocyclic compound is a cyclic compound in which one or more of the ring atoms is an
atom other than carbon. A ring atom that is not carbon is called a heteroatom.
 The name comes from the Greek word heteros, which means different. The most common
heteroatoms found in heterocyclic compounds are N, O, and S. Cyclic compounds that contain
at least one atom other than carbon within their ring are called Heterocyclic Compounds.
 Heterocyclic Compounds that possess aromatic stability are called Heterocyclic aromatic
Compounds.

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Nitrogen, oxygen and Sulfur are the most common heteroatoms found in aromatic compounds.
Pyridine has sp2 hybridized nitrogen:
 The p orbital on nitrogen is part of the aromatic system of the ring
 The nitrogen lone pair is in an sp2 orbital orthogonal to the p orbitals of the ring; these electrons
are not part of the aromatic system
 The lone pair on nitrogen is available to react with protons and so pyridine is basic
 Pyridine is nitrogen containing aromatic analogue of benzene.
 The N in pyridine is sigma bonded to two atoms and has a lone pair, and is therefore sp2
hybridized.
Pyridine is aromatic, and displays aromatic characteristics such as high resonance energy and
undergoes substitution as opposed to addition.
 The additional lone pair also adds new characteristics to pyridine.
 The lone pair makes pyridine capable of acting as a base.
 In the presence of acids, pyridine will become protonated, generating the
pyridinium ion.
 The pyridinium ion is still aromatic; the lone pair was not involved in the
aromatic 6π system. The proton is attached to the lone pair of the nitrogen.

Pyrrole
Pyrrole is a 5 membered heterocycle which is also aromatic. It contains 6 π electron, because the
Nitrogen can contribute its lone pair (2 electrons) to the π system, and thus create an aromatic.

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1.4. Aromatic Substitution Reactions and their Mechanism
The principal types of reactions involving aromatic rings are substitution, addition, and oxidation. Of
these, the most common type is electrophilic substitution. Most aromatic rings (benzene) are not
sufficiently nucleophilic to react with electrophiles. Catalysts are often needed to increase the reactivity
of the electrophiles.
Benzene does not undergo addition reactions like other unsaturated hydrocarbons, because
addition would yield a product that is not aromatic.
Substitution of a hydrogen keeps the aromatic ring intact.

Mechanism: a -bond of benzene acts as a nucleophile and attacks the electrophile leading to a
resonance stabilized cyclohexadienyl carbocation. This is relatively slow and endergonic because an
aromatic compound is being converted into a much less stable nonaromatic intermediate. Loss of a
proton gives the substitution product and restores aromaticity. This is fast and strongly exergonic
because the stability-enhancing aromaticity is being restored. The characteristic reaction of benzene is
electrophilic aromatic substitution—a hydrogen atom is replaced by an electrophile.
The most common electrophilic aromatic substitution reactions are: Halogenation (bromine (Br),
chlorine (Cl), or an iodine (I) substitutes for hydrogen), Nitration (A nitro group substitutes for a
hydrogen), Sulphonation (A sulphonic acid group substitutes for a hydrogen), Friedel–Crafts
acylation (An acyl group substitutes for a hydrogen) and Friedel–Crafts alkylation (an alkyl (R) group
substitutes for a hydrogen).

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 X
X2 , FeX3
Halogenation
+ HX (X=Cl, Br)

R
RCl, AlCl 3

Alkylation + HCl

NO 2
HONO 2 , H2SO 4

Nitration
+ H2O

SO 3H
SO 3 , H2SO 4
Sulfonation

Electrophile: a reagent that participates in a chemical reaction by accepting an electron pair in order
to bond to a nucleophile

1.4.1. Halogenation of benzene

The reaction of benzene with bromine or chlorine in the presence of a Lewis acid catalyst (such as
FeBr3, FeCl3 or AlCl3) leads to the formation of bromobenzene or chlorobenzene, respectively.

H Br
Br2, FeBr3
+ HBr

Nucleophile: is a reagent that forms a chemical bond to its reaction partner (the electrolyte) by
donating both bonding electrons.
Bromination Mechanism
In the first step of the bromination reaction, bromine donates a lone pair to the Lewis acid. This
weakens the Br-Br bond, thereby providing the electrophile necessary for electrophilic aromatic
substitution. The iron halides are Lewis acids and form complexes with the halogen atoms.
The formation of the bromine–iron (III) bromide complex increases the electrophilicity of the bromine
to the point that it can attack the benzene ring and form a δ complex. The next step, in which the -FeBr 4
ion removes the proton from the δ complex producing bromobenzene, HBr, and FeBr3, is quick.

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The order of reactivity of the halogens is F 2> C12> Br2> I2. Fluorine is too reactive to be of practical
use for the preparation of aromatic fluorine compounds and indirect methods are necessary. Iodine
usually is unreactive. It has been stated that iodination fails because the reaction is reversed as the
result of the reducing properties of the hydrogen iodide that is formed.
1.4.2. The Nitration of Benzene
Benzene reacts slowly with hot concentrated nitric acid in an electrophilic aromatic substitution
reaction to form nitrobenzene. A safer, faster, and more convenient synthesis employs a mixture of
concentrated nitric acid and concentrated sulphuric acid. Benzene can be nitrated using a mixture of
concentrated nitric (HNO3) and sulfuric (H2SO4) acid.

NO 2
HNO3, H2SO4
+ H 2O

Formation of electrophile
+ -
HNO3 + H2SO4 NO2 + H2O + HSO4

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Nitration Mechanism
To generate the necessary electrophile, sulfuric acid protonates nitric acid. Loss of water from
protonated nitric acid forms a nitronium ion, the electrophile required for nitration. Remember that any
base present in the reaction mixture (solvent) can remove the proton in the second step of the aromatic
substitution reaction. The concentrated sulfuric acid acts as a catalyst allowing nitration to take place
more readily at more moderate temperatures.

1.4.3. Sulfonation of Benzene

Fuming sulfuric acid (a solution of in sulfuric acid) or concentrated sulfuric acid is used to sulfonate
aromatic rings. A sulfonic acid is a strong acid because of the three electron-withdrawing oxygen
atoms and the stability of its conjugate base—the electrons left behind when a proton is lost are shared
by three oxygen atoms.
Sulfur trioxide (rather than protonated sulfur trioxide) could also act as the electrophile in these
reactions. Sulfonation of benzene is a reversible reaction.

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Desulfonation

1.4.4. Friedel-Crafts Acylation of benzene

Friedel–Crafts acylation places an acyl group on a benzene ring, and Friedel– Crafts alkylation
places an alkyl group on a benzene ring.
A Friedel-Crafts acylation reaction involves the reaction of an acyl halide or an acid anhydride
and a Lewis acid with benzene to yield acyl benzene. Both the acyl halide and the anhydride
work well in this reaction because each possesses a good leaving group.
The acyl halide has a halide ion leaving group and the acid anhydride has a carboxylate ion
leaving group.
The Friedel Crafts acylation produces a deactivated ring (ketone) and, because deactivated rings
cannot undergo a second acylation, the reaction stops at that point. The reaction of benzene
with acid chlorides in the presence of a Lewis acid catalyst (such as FeCl 3 or AlCl3) leads to the
formation of acyl benzenes.

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Mechanism
1st, Formation of Electrophile
Aluminum chloride first forms an acid/base complex with the carbonyl group of the acyl halide. The
acid/base complex is relatively stable in low polarity solvents. In higher polarity solvents, however, it
ionizes and forms a resonance-stabilized acyl (or acylium) cation.

O
O
+ -
C   C
R Cl AlCl3 R C O AlCl4
R
acylium ion

2nd Acylation Mechanism

An acyl cation reacts with benzene in much the same way as any other electrophile.

Chemists use anhydrides to generate the acylium ion less frequently than they use acyl halides because
only a few anhydrides are commonly available. In addition, acid anhydrides are expensive and only
half the material is available for reaction.

1.4.5. Friedel-Crafts Alkylation of benzene

It is one of the most useful synthetic methods in organic chemistry because it allows the introduction of
a carbon side chain to benzene. The formation of alkyl benzene in a Friedel Crafts alkylation involves

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benzene, an alkyl halide, and a Lewis acid. Aluminum chloride is commonly used as the Lewis acid,
accepting a pair of electrons from the halogen atom.

R
RX, AlCl 3
+ HCl

Mechanism

CH3 CH3
CH3 C Cl AlCl3 CH3 C AlCl4
CH3 CH3
t-butyl carbocation

CH3 (CH3)3C (CH3)3C (CH3)3C

CH3 C
H
CH3
resonance stabilized intermediate
Cl AlCl3
(CH3)3C
+ HCl
(+ AlCl 3)

1.4.6. Directing Effects of Substituents

When two substituents are present on benzene ring their position may be indicated by the prefixes
ortho, meta and para (o, m and p) or by the corresponding numerical positions.
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  Substituents that are capable of donating electrons into the benzene ring will stabilize both the
carbocation intermediate and the transition state leading to its formation, thereby increasing
the rate of electrophilic aromatic substitution.
 In contrast, substituents that withdraw electrons from the benzene ring will destabilize the
carbocation intermediate and the transition state leading to its formation, thereby decreasing
the rate of electrophilic aromatic substitution.
 Electron-donating substituents increase the reactivity of the benzene ring toward electrophilic
aromatic substitution. Electron-withdrawing substituents decrease the reactivity of the benzene
ring toward electrophilic aromatic substitution.
 The activating substituents make the benzene ring more reactive toward electrophilic
substitution are those donating electrons into the ring.
 The deactivating substituents make the benzene ring less reactive toward electrophilic
substitution are those withdraw electrons from the ring.
Orientation and Reactivity Effects of Substitution in benzene ring in Electrophilic Aromatic
Substitution

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Orientation Effects in Substituted Benzenes
There are two general types of ortho-para directors and one general type of meta director.
 All ortho-para directors are R groups or have a non-bonded electron pair on the atom bonded to
the benzene ring.
 All Meta directors have a full or partial positive charge on the atom bonded to the benzene ring.
Ortho-para directing substituents
Activators: Substituents that make benzene MORE REACTIVE donate electrons into the benzene
ring.
 Increase benzene nucleophilicity (more reactive towards electrophiles)
 stabilizes carbocation intermediate
 stabilizes transition state leading to carbocation formation
 faster reaction rate for electrophilic attack
Deactivators: Substituents that make benzene LESS REACTIVE withdraw electrons from the benzene
ring;
decrease benzene nucleophilicity (less reactive towards electrophiles)
destabilize carbocation intermediate (increases the net positive charge on the carbocation)
destabilize transition state leading to carbocation formation
slower rate of electrophilic attack
All ortho/para directors are activators, except for halides.
All meta directors are deactivators, no exceptions.

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1. Propose a synthesis for each of the following substituted aromatics.
A) tert-Butylbenzene B) 2-Methyl-1-phenylpropane C) Butylbenzene D) Toluene
1.4.7. Representative Reactions of pyrrole, furan, thiophene and pyridine
Pyrrole, furan, and thiophene are five-membered-ring heterocycles. Each has three pairs of delocalized
 electrons: Two of the pairs are shown as  bonds, and one pair is shown as a 13 lone pair on the
heteroatom. Because pyrrole, furan, and thiophene are aromatic, they undergo electrophilic aromatic
substitution reactions. They undergo electrophilic substitution preferentially at C-2. Substitution occurs
preferentially at C-2 because the intermediate obtained by attaching a substituent at this position is
more stable than the intermediate obtained by attaching a substituent at C-3.

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Mechanisms for electrophilic aromatic substitution
Pyrrole: General mechanism

Relative reactivity toward electrophilic aromatic substitution

Furan is not as reactive as pyrrole in electrophilic aromatic substitution reactions. The oxygen of furan
is more electronegative than the nitrogen of pyrrole, so the oxygen is not as effective as nitrogen in
stabilizing the carbocation. Thiophene is less reactive than furan toward electrophilic substitution
because sulfur’s  electrons are in a 3p orbital, which overlaps less effectively than the 2p orbital of
nitrogen or oxygen with the 2p orbital of carbon.
Pyridine: General mechanism

Where is the preferred substitution site?

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Pyridine does not undergo Friedel–Crafts alkylation because its reactivity is highly affected by
electronegative nitrogen. Therefore, undergoes electrophilic aromatic substitution reactions only under
vigorous conditions (very high T), and the yields of these reactions are often quite low.
1.5. Nucleophilic Aromatic Substitution Reactions
As you may know that, aryl halides do not react with nucleophiles under standard reaction conditions
because the π electron clouds repel the approach of a nucleophile.
1.5.1. Reactions of Aryl halides
However, when the aryl halide has one or more substituents that strongly resonate electrons from the
ring, nucleophilic aromatic substitution reactions can occur without the use of extreme conditions. The
electron-withdrawing groups must be ortho or para to the halogen. The larger the number of electron-
withdrawing substituents, the easier it is to carry out the nucleophilic aromatic substitution reaction.
Note the different conditions under which the following reactions occur. Examples:

Electron-withdrawing substituents increase the reactivity of the benzene ring toward nucleophilic
substitution and decrease the reactivity of the benzene ring toward electrophilic substitution.
1.5.2. Mechanisms of Nucleophilic Aromatic Substitution Reactions
Nucleophilic aromatic substitution takes place by a two-step reaction known as a SNAr reaction
(Substitution nucleophilic aromatic). In the first step, the nucleophile attacks the carbon bearing the

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leaving group from a trajectory that is nearly perpendicular to the aromatic ring. Nucleophilic attack
forms a resonance-stabilized carbanion intermediate called a Meisenheimer complex, after Jakob
Meisenheimer (1876–1934). In the second step of the reaction, the leaving group departs, re-
establishing the aromaticity of the ring.
Mechanism for nucleophilic aromatic substitution

In a nucleophilic aromatic substitution reaction, the incoming nucleophile must be a stronger base than
the substituent that is being replaced, because the weaker of the two bases will be the one eliminated
from the intermediate. The electron-withdrawing substituent must be ortho or para to the site of
nucleophilic attack because the electrons of the attacking nucleophile can be delocalized onto the
substituent only if the substituent is in one of those positions.

1.6. Reactions of Aromatic Side Chains

1.6.1. Oxidation and Substitution of Alkyl Side-Chains
Oxidation reactions of alkyl side chain
An alkyl group bonded to a benzene ring can be oxidized to a carboxyl group. When an organic
compound is oxidized, either the number of C-O, C-N, or C-X (where X denotes a halogen atom)
bonds increases or the number of C-H bonds decreases. Commonly used oxidizing agents are
potassium permanganate (KMnO4) or acidic solutions of sodium dichromate (H +, Na2Cr2O7) because
the benzene ring is so stable, it will not be oxidized— only the alkyl group is oxidized.

Alkyl side chain react rapidly with oxidizing agents and are converted into carboxyl groups. Regardless
of the length of the alkyl substituent, it will be oxidized to a -COOH group, provided that a hydrogen is
bonded to the benzylic carbon. If the alkyl group lacks a benzylic hydrogen, the oxidation reaction will

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not occur because the first step in the oxidation reaction is removal of a hydrogen from the benzylic
carbon.

The mechanism is slightly complicated, and you’re not expected to know it. When two alkyl groups are
present on the ring, both are oxidized.

Note that alkyl groups, regardless of their chain length, are converted to carboxyl groups (- CO 2H)
attached directly to the ring. An exception is a substituent of the type -CR 3 because it lacks benzylic
hydrogens, such a group is not susceptible to oxidation under these conditions.

Despite its unsaturation, the benzene ring is inert to strong oxidizing agents such as KMnO 4 and
Na2Cr2O7 that will cleave alkene C-C bonds.

KMnO4
no product
H2O

But oxidizing agent oxidizes alky substituent on benzene to carboxylic acid.

Radical halogenation of alkyl side chain
Alkyl benzene undergo free radical halogenation much more easily than alkanes. Why? Because
abstraction of hydrogen atom at a benzylic position gives a resonance stabilized benzylic radical.
Example, ethylbenzene reacts with chlorine in the presence of light to give α-chlorobenzene. The
reaction can possibly give mixture of α-chlorobenzene (major), β-chlorobenzene because chlorine
radical is very reactive. Further oxidation may also result dichlorobenzene. But bromine (using Br 2 or
NBS with hv) reacts exclusively at the benzylic position. Why? B/c bromine is less reactive than
chlorine.
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N-Bromosuccinimide (NBS) can brominate or chlorate at the benzylic position via a free radical chain
mechanism (i.e. at the carbon atom attached to the benzene ring). It should be noted that the
intermediate benzylic radical is stabilized by resonance (i.e. the radical can interact with the p-electrons
of the benzene ring).

Br

N
O O

N-Bromosuccinimide

1.6.2 Reduction of Nitro Groups and Aryl Ketones

Reducing a nitro substituent
A nitro substituent can be reduced to an amino substituent. Either a metal (tin, iron, or zinc) plus an
acid (HCl) or catalytic hydrogenation can be used to carry out the reduction. If acidic conditions are
employed, the product will be in its acidic form (anilinium ion). When the reaction is over, base can be
added to convert the product into its basic form (aniline).

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It is possible to selectively reduce just one of two nitro groups.

Reducing aryl ketones

There are more general methods available to reduce a ketone carbonyl group to a methylene group—
methods that reduce all ketone carbonyl groups, not just those that are adjacent to benzene rings. Two
of the most effective are the Clemmensen reduction and the Wolff– Kishner reduction. The
Clemmensen reduction uses an acidic solution of zinc dissolved in mercury as the reducing reagent.
The Wolff–Kishner reduction employs hydrazine under basic conditions. Generally, Clemmensen and
Wolff–Kishner reductions can be represented as:

Mechanism of Wolff-Kishner reduction reaction

1.6.3 Conversion of Halogens to Organometallic Reagents

Organometalic reagents can be can be prepared from benzene by:

Hence, this organometallic reagent is important to prepare other aromatic derivatives. Examples:

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1.6.4 Hydrolysis and Fusion of Sulphonic Acids
Sulfonic acids are not very important by themselves. However, it is usually easy to convert sodium
salts of sulfonic acids into phenolic compounds which do have great synthetic, commercial, and
biological importance. This reaction is carried out by melting or ''fusing'' the sulfonic acid in the
presence of NaOH and/or KOH. Although the conditions seem drastic, the yields are often quite good.
Examples:

1.6.5 Modifying the Influence of Strong Activating Groups

Aryl amines and phenols are so reactive towards electrophilic aromatic substitution that multiple
halogenation occurs. Example:

In order to prepare p-bromoaniline, aniline must be acylated with acetyl chloride. The acylated group is
important to direct the coming group preferentially to the para position b/c of its steric effect on the
ortho. substituents are less effective at donating electrons into the ring by resonance because, unlike the
strongly activating substituents that donate electrons by resonance only into the ring, the moderately
activating substituents can donate electrons by resonance in two competing directions: into the ring and
away from the ring.

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Nevertheless, the amide group is still ortho-para directing and activating and the amino group is
reformed by the hydrolysis of the amide.

1.6.6 Diazotization of Primary Aromatic Amines and their Usefulness in Synthesis of Aromatic
Derivatives
A primary amine can be converted into a diazonium salt by treatment with nitrous acid because nitrous
acid (HNO2). is unstable, it is formed in situ, using an aqueous solution of sodium nitrite and HCl or
HBr; indeed, N2 is such a good leaving group [NH2] that the diazonium salt is synthesized at 0 °C and
used immediately without isolation. (The mechanism for conversion of a primary amino group [+N≡N]
to a diazonium group is shown below. The reaction of aromatic amines with the nitrosonium ion (+NO)
that generated from nitrous acid (HNO2) or NaNO2 and HCl, yields aryl diazonium salts, which can be
converted (on loss of nitrogen) to a range of functional groups.

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On heating, the aryl diazonium ion can produce nitrogen gas (an excellent leaving group) and a very
unstable aryl cation in an SN1 mechanism, which can react with nucleophiles.
The mechanism by which a nucleophile displaces the diazonium group depends on the nucleophile:
Some displacements involve phenyl cations, while others involve radicals.
Most azo compounds are highly colored and make excellent dyes. These dyes, called azo dyes, are
usually more stable and retain their bright colors better than most other dyes.
Following are a few examples of azo dyes.

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Page 32 by Gedefa Dinsa OBU
2. AMINES
They are an important class of organic compounds in which one or more of the hydrogen of ammonia
have been replaced by alkyl groups or aryl groups. Amines, like ammonia, are weak bases (Kb = 10 -4 to
10-6). This basicity is due to the unshared electron pair on the nitrogen atom. Their ultimate source is
atmospheric nitrogen which, by a process known as nitrogen fixation, is reduced to ammonia, then
converted to organic nitrogen compounds. They are also essential to life. In nature, they occur among
proteins, vitamins, alkaloids and hormones. Synthetic examples include polymers, dyestuffs and drugs.
 Like ammonia, nitrogen atom of amine is:
 Trivalent and carries an unshared pair of electrons.
 Nitrogen orbitals in amines are therefore,
 sp3 hybridized and the geometry of amines is pyramidal.
Amines are classified as primary (1 o), secondary (2o) and tertiary (3o) depending upon the number of
hydrogen atoms replaced by alkyl or aryl groups in ammonia molecule.
 If one hydrogen atom of ammonia is replaced by R or Ar, we get RNH 2or ArNH2, a primary
amine (1o).
 If two hydrogen atoms of ammonia or one hydrogen atom of R-NH2 are replaced by another
alkyl/aryl (R’) group, you get R-NHR‘, secondary amine.
 The second alkyl/aryl group may be same or different. Replacement of another hydrogen atom
by alkyl/aryl group leads to the formation of tertiary amine. Amines are said to be simple when
all the alkyl or aryl groups are the same, and mixed when they are different.

The amine nitrogen atom has a non-bonded electron pair, making it both a base and a
nucleophile. As a result, amines react with electrophiles to form quaternary.

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 2.1 Structure & Nomenclature
Structure of Amines
N is sp3-hybridized C–N–C bond angles are close to 109.5° tetrahedral value. The unshared
electron pair around nitrogen - along with the three groups results in a tetrahedral geometry.
 The nitrogen of an amine has the same geometry like ammonia. One, two, or three hydrogens
may be replaced by alkyl groups.
 The number of hydrogens replaced by alkyl groups determines whether the amine is primary,
secondary, or tertiary.

Amines are further divided into aliphatic, aromatic, and heterocyclic amines:
 Aliphatic amine: an amine in which nitrogen is bonded only to alkyl groups.
 Aromatic amine: an amine in which nitrogen is bonded to one or more aryl groups.
 Heterocyclic amine: an amine in which nitrogen is one of the atoms of a ring.
Nomenclature of amines
 Simple 1°, 2°, and 3° amines:
 Common names: - are obtained by alphabetically arranging the names of the alkyl
substituents on the nitrogen and adding the suffix –amine.

Amines in the IUPAC system:

 Pick out the longest continuous chain of carbon atoms. The parent name comes from the alkane
of the same number of carbons.
 The “e” ending of the alkane name for the longest chain is replaced with –amine.
 Groups that are attached to the nitrogen atom are located using “N” as the position number.
 The name of any alkyl group bonded to nitrogen is preceded by an “N” (in italics) to indicate
that the group is bonded to a nitrogen rather than to a carbon.

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 Aromatic amines belong to specific families, which act as parent molecules. For example, an amino
group (—NH2) attached to benzene produces the parent compound aniline.

2.2. Properties of Amines: Physical and Chemical properties

The lower aliphatic amines are gases with fishy odor. Primary amines with three or more carbon atoms
are liquid and still higher ones are solid. Aniline and other arylamines are usually colorless, but get
colored on storage due to atmospheric oxidation. Lower aliphatic amines are soluble in water because
they can form hydrogen bonds with water molecules. However, solubility decreases with increase in
molar mass of amines due to increase in size of the hydrophobic alkyl part. Higher amines are
essentially insoluble in water. Alcohols are more polar than amines and form stronger intermolecular
hydrogen bonds than amines.
We have often seen that the polar nature of a substance can affect physical properties such as boiling
point. This is true for amines, which are more polar than alkanes but less polar than alcohols. For
similarly constituted compounds, alkyl amines have boiling points higher than those of alkanes but
lower than those of alcohols.

CH3CH2CH3 CH3CH2NH2 CH3CH2OH

Propane Ethylamine ethanol

μ=0D μ = 1.2 D μ = 1.7 D
bp -42oC bp 17oC bp 78oC

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Dipole-dipole interactions, especially hydrogen bonding, are present in amines but absent in
alkanes. But because nitrogen is less electronegative than oxygen, an N-H bond is less polar than
an O-H bond and hydrogen bonding is weaker in amines than in alcohols. Among isomeric
amines, primary amines have the highest boiling points, and tertiary amines the lowest.
CH3CH2CH2NH2
Example:
CH3CH2NHCH3 (CH3)3N
bp 50oC bp 34oC bp 3oC

Therefore, the order of boiling points of isomeric amines is as follows: Primary> Secondary > Tertiary.
Tertiary amines, like primary and secondary amines, have lone-pair electrons that can accept hydrogen
bonds, but unlike primary and secondary amines, tertiary amines do not have hydrogens to donate for
hydrogen bonds. Amines that have fewer than six or seven carbon atoms are soluble in water. The
simplest arylamine, aniline, is a liquid at room temperature and has a boiling point of 184 oC. Almost all
other arylamines have higher boiling points. Aniline is only slightly soluble in water (3 g/100mL).

Comparing amines with the same number of carbons, we find that primary amines are more soluble
than secondary amines because primary amines have two hydrogens that can engage in hydrogen
bonding. Tertiary amines, therefore, are less soluble in water than are secondary amines with the same
number of carbons.
Amines act as a base due to lone pairs of electrons on nitrogen. They also can act as nucleophile in
different reactions i.e. they are reactive relative to other organic compounds like alkanes.
2.3. Basicity of Nitrogen Compounds
The nitrogen atom of amines has a lone pair of electrons, and this gives rise to characteristics of
nucleophilicity and basicity. The lone pair of electrons on nitrogen makes amines basic and
nucleophilic. These unshared electrons create an electron density around the nitrogen atom. The greater
the electron density present, the more basic the molecule. Groups that donate or supply electrons will

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increase the basicity of amines while groups that decrease the electron density around the nitrogen
decrease the basicity of the molecule.
For alkyl amines in the gas phase, the order of base strength is given below:

However, in aqueous solutions, the order of basicity changes,

They react with acids to form acid–base salts and they react with electrophiles in many polar reactions.
Amines are stronger bases than alcohols, ether or water. Because, Amines establish equilibrium with
water in which the amine becomes protonated and hydroxide is produced. The most convenient way to
measure the basicity of an amine (RNH 2) is to look at the acidity of the corresponding ammonium ion
(RNH3+) high pKa → weaker acid and stronger conjugate base.

Aryl amines and heterocyclic aromatic amines are considerably less basic than alkyl amines
(conjugate acid pKa=5 or less) because of resonance. Aniline, a typical arylamine, exhibits the
resonance structures shown.

As there is delocalization of the unshared electron pair throughout the ring, the electrons will be
less available for reaction. As a result, the molecule becomes less basic.

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Amines act as base and also as nucleophile as below;
 Amine as a nucleophile:

 Amine as a base:

Amines are basic, and therefore their aqueous solutions are basic (pH>7), and recall that base strength
is talked of in terms of base-dissociation constant (Kb). The values of Kb for most amines are small
(10-3), but still basic.
There are many factors that influence base strength;
(a) Alkyl group substitution
If we consider the relative basicity‘s ammonia and methylamine, then we might expect the electron
donating abilities of the alkyl group to help to stabilize the ammonium cation produced, thus making
methylamine a stronger base than ammonia.

This is indeed the case;

 However the above logic implies that secondary amines should be stronger bases than
primary amines, and those tertiary amines the strongest bases of all.

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 (b) Resonance Effects
Aromatic amines, such as aniline, are weaker bases than normal aliphatic amine. This is due to the fact
that the lone pair of electrons on the nitrogen is delocalized into the aromatic  system. This stabilizes
the free amine, and therefore makes the transition to the protonated form more endothermic than the
aliphatic case - and thus less energetically favorable.
The stabilizing overlap in aniline makes the lone pair less reactive, therefore a weaker base.
(c) Hybridization Effects
Electrons held in orbitals that have more s character are held more tightly. Therefore a lone pair held
in a sp orbital will be more strongly held (i.e. less basic) than a lone pair held in a sp3 orbital. E.g.
Acetonitrile, Pyridine, and Piperidine.

d) Steric and electronic effects

The difference in basicity between ammonia, and primary, secondary, and tertiary alkylamines
result from the interplay between steric and electronic effects on the molecules themselves and on
the salivation of their conjugate acids. In total, the effects are small, and most alkylamines are very
similar in basicity. In water, the ammonium salts of primary and secondary amines undergo
solvation effects (due to hydrogen bonding) to a much greater degree than ammonium salts of
tertiary amines. These solvation effects increase the electron density on the amine nitrogen to a
greater degree than the inductive effect of alkyl groups. Alkyl groups donate electrons to nitrogen
cations formed during the acid base reaction and thus they can stabilize the positive charge. But
steric crowding of tertiary amines is where a reactive site is difficult to reach because of the alkyl
groups surrounding it. This crowding decreases the number of water molecules that can be
involved in stabilizing the ion. As a result, trimethylamine is less basic than either dimethylamine
or methylamine.
2.4. Acidity of Nitrogen Compounds
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Primary and secondary amines are very weak acids. The lithium salts of such amines can be
prepared in ether solution by treatment of the amine with phenyl lithium:

The lithium salt of N-ethylethanamine (diethylamine) is called lithium diethylamide, but this
nomenclature can lead to confusion with compounds of the type RCO 2NH, which are derived from
carboxylic acids and also are called amides. Alkanamines have acid strengths corresponding to Ka
values of about l0-33, which means that their conjugate bases are powerfully basic reagents.
Therefore they are very effective in causing elimination reactions by the E 2 mechanism and
aromatic substitution by the aryne mechanism. The following example illustrates this property in a
useful synthesis of a benzenamine from bromobenzene:

Exercise
1. a. Explain why 1, 3-diazacyclopentadiene (imidazole) is a much stronger acid than
azacyclopentadiene (pyrrole).

2. Would you expect benzenamine to be a stronger or weaker acid than cyclohexanamine?

Give your reasoning.

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 2.5. Reactions of Amines
Both the basicity and the nucleophilicity of amines originate in the unshared electron pair of nitrogen.
When an amine acts as a base, this electron pair abstracts a proton from a Brønsted acid. Amines react
as nucleophiles with electrophilic carbon atoms.
o Amines attack carbonyl groups to form products of nucleophilic addition or substitution.
o The first step in the reaction of amines is the attack of the unshared electron pair on the

positively polarized carbon of a carbonyl group.

Primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide.
Alkylations of primary and secondary amines are difficult to control and often give mixtures of
products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. The reaction of
ammonia with an alkyl halide leads to the formation of a primary amine. The primary amine that is
formed can also react with the alkyl halide, which leads to a disubstituted amine that can further react
to form a trisubstituted amine. Therefore, the alkylation of ammonia leads to a mixture of products.

Example;

Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution
reaction with an acid chloride or an acid anhydride to yield amides. Note that overacylation of the

Page 41
nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the
starting amine

Example;

Reaction of Amines with Nitrous Acid: We have seen (in chapter 1) that the reaction of a
primary amine with nitrous acid produces a diazonium salt. Both aryl amines and alkyl
amines undergo this reaction, and both follow the same mechanism.

Conversion of a primary amino group to a diazonium group requires a nitrosonium ion that
is formed when water is eliminated from protonated nitrous acid.

The nitrosonium ion accepts a share of the amino nitrogen’s lone pair. Loss of a proton from
nitrogen forms a nitrosamine (also called an N-nitroso compound because a nitroso
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 substituent is bonded to a nitrogen). Delocalization of nitrogen’s lone pair and protonation of
oxygen form a protonated N-hydroxy azo compound. This compound is in equilibrium with
its non-protonated form, which can be reprotonated on nitrogen (reverse reaction) or
protonated on oxygen (forward reaction). Elimination of water forms the diazonium ion.
Remember that reactions in which arenediazonium ions are involved must be carried out at 0
°C because they are unstable at higher temperatures. Alkanediazonium ions are even less
stable. They lose molecular N2 even at 0 °C as they are formed, reacting with whatever
nucleophiles are present in the reaction mixture by both E1/S N1 and E2/SN2 mechanisms.
Because of the mixture of products obtained, alkanediazonium ions are of limited synthetic
use.

Secondary aryl and alkyl amines react with a nitrosonium ion to form nitrosamines rather than
diazonium ions. The mechanism of the reaction is similar to that for the reaction of a primary
amine with a nitrosonium ion, except that the reaction stops at the nitrosamine stage. The reaction
stops because a secondary amine, unlike a primary amine, does not have the second proton that
must be lost in order to generate the diazonium ion.

The product formed when the nitrogen of a tertiary amine shares its lone pair with a nitrosonium
ion cannot be stabilized by loss of a proton. A tertiary aryl amine, therefore, can undergo an
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electrophilic aromatic substitution reaction with a nitrosonium ion. The product of the reaction is
primarily the para isomer because the bulky dialkylamino group blocks approach of the
nitrosonium ion to the ortho position.

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 Reaction with aldehydes and ketones:
Primary amines, RNH2, add to aldehydes and ketones to yield imines, R2C=NR. Secondary
amines, R2NH, add similarly to yield enamines, R2N-CR=CR2 (unsaturated amine).

Imine formation and enamine formation appear different because one leads to a product with a C=N
bond and the other leads to a product with a C=C bond. Actually, though, the reactions are quite
similar. Both are typical examples of nucleophilic addition reactions in which water is eliminated from
the initially formed tetrahedral intermediate and a new C=Nu bond is formed. An imine is formed in a
reversible, acid-catalyzed process that begins with nucleophilic addition of the primary amine to the
carbonyl group, followed by transfer of a proton from nitrogen to oxygen to yield a neutral amino
alcohol, or carbinolamine.
Protonation of the carbinolamine oxygen by an acid catalyst then converts the –OH into a better
leaving group (–OH2+), and E1-like loss of water produces an iminium ion. Loss of a proton from
nitrogen gives the final product and regenerates the acid catalyst.
Reaction of an aldehyde or ketone with a secondary amine, R2NH, rather than a primary amine

Page 45
yields an enamine. The process is identical to imine formation up to the iminium ion stage, but at
this point there is no proton on nitrogen that can be lost to form a neutral imine product. Instead, a
proton is lost from the neighboring carbon (the α-carbon), yielding an enamine.
Reaction of NH3 and 1o and 2o amines with acid chlorides and anhydrides

2.6 Electrophilic Substitution at Nitrogen

 Ammonia and many amines are not only bases in the Brønsted sense; they are also nucleophiles
that bond to and form products with a variety of electrophiles.
 A list of some electrophiles that are known to react with amines is shown here. In each case the
electrophilic atom or site is bold or red colored.

 Direct nitration of aniline and other arylamines, is difficult to carry out. Thus, protecting the
amino group of an arylamine moderates its reactivity and permits nitration of the ring to be
achieved.

2.6. Preparation of 1o, 2o& 3o Amine

Because ammonia and amines are good nucleophiles, they readily undergo SN2 reactions with
Alkyl halides. (X denotes a halogen.)

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Although these SN2 reactions can be used to synthesize amines, the yields are poor because it
is difficult to stop the reaction after a single alkylation since ammonia and primary,
secondary, and tertiary amines have similar reactivity’s. Therefore, the alkylation of ammonia
leads to a mixture of products.
A much better way to prepare a primary amine is by means of a Gabriel synthesis. This
reaction involves alkylating phthalimide and then hydrolyzing the N-substituted phthalimide.

Primary amines also can be prepared in good yields if azide ion (-N3) is used as the
nucleophile in an SN2 reaction. The product of the reaction is an alkyl azide, which can be
reduced to a primary amine.

Other reduction reactions also result in the formation of primary amines. For example, the
catalytic reduction of a nitrile forms a primary amine. (Recall that a nitrile can be obtained
from the reaction of cyanide ion with an alkyl halide.)

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 Amines are obtained from the reduction of amides with LiAlH 4. This method can be used to
synthesize primary, secondary, and tertiary amines. The class of amine obtained depends on
the number of substituents on the nitrogen atom of the amide.

A primary amine can be obtained from the reaction of an aldehyde or a ketone with excess
ammonia in the presence of H 2 and Raney nickel. Because the imine does not have a
substituent other than a hydrogen bonded to the nitrogen, it is relatively unstable, so the amine
is obtained by H2 adding to the C=N bond as it is formed. This is called reductive amination.

Secondary and tertiary amines can be prepared from imines and enamines by reducing the imine or
enamine. Sodium triacetoxyborohydride is a commonly used reducing agent for this reaction.

Reduction of nitrocompounds: A primary amine is obtained from the reduction of a nitroalkane, and
an arylamine is obtained from the reduction of nitrobenzene. Aromatic amines are normally prepared
by reduction of the corresponding aromatic nitro compound

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Reduction of nitriles
Nitriles on reduction with lithium aluminium hydride (LiAlH4) or catalytic hydrogenation
produce primary amines.
Nitriles can be produced by SN2 reaction of alkyl halides.
Reduction produces the corresponding amines.

Reduction of Amides
Amides can also be reduced to the corresponding amines using LiAlH4.

2.7. Reactions of Aryl Diazonium Intermediates (See Diazotization Reactions)

Diazonium salts of aromatic amines are very useful as intermediates to other compounds.
Because aromatic diazonium salts are only stable at very low temperatures (zero degrees and
below), warming these salts initiates decomposition into highly reactive cations. These
cations can react with any anion (nucleophile) present in solution to form a variety of
compounds. Generally,

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2.8. Elimination Reactions of Amines (Hofmann Eliminations)
 The halide anion of quaternary ammonium iodides may be replaced by hydroxide by treatment
with an aqueous slurry of silver oxide.
 Silver iodide precipitates, and a solution of the quaternary ammonium hydroxide is formed.

 When quaternary ammonium hydroxides are heated, they undergo elimination to form an
alkene and an amine.

 This reaction is known as the Hofmann elimination; it was developed by August [Link] in
the middle of the nineteenth century and is both a synthetic method to prepare alkenes and an
analytical tool for structure determination.
 A novel aspect of the Hofmann elimination is its regioselectivity.
 Regioselective reaction means the reaction in which more than one site attack is
possible, but occur through preferentially attack one site only, to produce a prevalent,
one of the isomeric product.

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The least sterically hindered hydrogen is removed by the base in Hofmann elimination reactions
(E2). Methyl groups (CH3) are deprotonated in preference to methylene groups (CH 2), and
methylene groups are deprotonated in preference to methines (CH).

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3. REACTIONS OF CARBONYL COMPOUNDS
The carbonyl group is a carbon double bonded to oxygen and is probably the most important
functional group found in organic compounds. Compounds containing carbonyl groups are called
carbonyl compounds and are abundant in nature. Carbonyl compounds play important roles in
biological processes. Hormones, vitamins, amino acids, drugs, and flavourings are just a few of the
carbonyl compounds that affect us daily. An acyl group consists of a carbonyl group attached to an
alkyl group or to an aryl group. Carbonyl compounds can be placed in one of two classes: those that
contain a group that can be replaced by another group (Class I) and those that do not contain a group
that can be replaced by another group (Class II).
Class I carbonyl compounds are those in which the acyl group is attached to an atom or a group
that can be replaced by another group. Carboxylic acids, acyl halides, acid anhydrides, esters, and
amides belong to this class. All of these compounds contain a group (–OH, –Cl, – Br, –O (CO) R,
–OR, –NH2, –NHR, or –NR2, that can be replaced by a nucleophile. Acyl halides, acid
anhydrides, esters, and amides are all called carboxylic acid derivatives because they differ from
a carboxylic acid only in the nature of the group that has replaced the OH group of the carboxylic

acid.

Class II carbonyl compounds are those in which the acyl group is attached to a group that cannot
be readily replaced by another group. Aldehydes and ketones belong to this class. The–H and alkyl
or aryl (–R or –Ar) groups of aldehydes and ketones cannot be replaced by a nucleophile.
The reactions of carbonyl compounds are one of the most important class of synthetically useful
reaction in organic chemistry. The carbonyl functional group is also regarded as the most important
functional group that participate in multiple modes of reactions. The reactions of carbonyls can be
broadly classified as the direct nucleophilic addition reactions where in a nucleophile adds to the

carbonyl carbon atom. The carbonyl C=O bond is polarized, and the oxygen atom is slightly negative,

Page 52
while the carbon atom is slightly positive (electron deficient or electrophile). Therefore the carbonyl
carbon can be easily attacked by nucleophile (Nu -) or electron rich species in nucleophilic addition
reactions.
Nucleophile can be either negatively charged (-:Nu) or neutral (:Nu). If it’s neutral, however,
it usually carries a hydrogen atom that can subsequently be eliminated, :Nu–H. For example:
The weaker the basicity of a group, the better will be its leaving ability.

Carbonyl compounds undergoes three main kinds of reactions:

 Nucleophilic addition reactions
 Addition-Elimination
 Enolization-Ketonization
3.1. Nucleophilic Addition Reactions
Both charged and uncharged nucleophiles add to the carbonyl carbon atom to form addition products.
This reaction is catalyzed either by base or an acid. With charged nucleophiles under base catalysis:
Addition of the elements of water.

Example of Nucleophilic Carbonyl Addition Reactions

3.1.1. Hydrate Formation

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Water adds to an aldehyde or a ketone to form a hydrate. A hydrate is a molecule with two OH groups
on the same carbon. Hydrates are also called gem-diols (gem comes from geminus, Latin for ―twin).
Hydrates of aldehydes or ketones are generally too unstable to be isolated because the tetrahedral
carbon is attached to two oxygen [Link] is catalysed by acid b/c of weak nucleophilic nature
of water.

Water is a poor nucleophile and therefore adds relatively slowly to a carbonyl group. The rate
of the reaction can be increased by an acid catalyst keep in mind that a catalyst has no effect
on the position of the equilibrium.
Mechanism for acid-catalyzed hydrate formation

3.1.2. Hemiacetal and Hemiketal Formation

The product formed when one equivalent of an alcohol adds to an aldehyde is called a
hemiacetal. The product formed when a second equivalent of alcohol is added is called an
acetal. Like water, an alcohol is a poor nucleophile, so an acid catalyst is required for the
reaction to take place at a reasonable rate.

When the carbonyl compound is a ketone instead of an aldehyde, the addition products are
called a hemiketal and a ketal, respectively.

Hemi is the Greek word for ―half. When one equivalent of alcohol has added to an aldehyde
or a ketone, the compound is halfway to the final acetal or ketal, which contains groups from
two equivalents of alcohol.

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In the first step of acetal (or ketal) formation, the acid protonates the carbonyl oxygen, making
the carbonyl carbon more susceptible to nucleophilic attack. Loss of a proton from the
protonated tetrahedral intermediate gives the hemiacetal (or hemiketal). Because the reaction
is carried out in an acidic solution, the hemiacetal (or hemiketal) is in equilibrium with its
protonated form. The two oxygen atoms of the hemiacetal (or hemiketal) are equally basic, so
either one can be protonated. Loss of water from the tetrahedral intermediate with a
protonated OH group forms a compound that is very reactive because of its electron-deficient
carbon. Nucleophilic attack on this compound by a second molecule of alcohol, followed by
loss of a proton, forms the acetal (or ketal).

Mechanism for acid-catalyzed acetal or ketal formation

Although the tetrahedral carbon of an acetal or ketal is bonded to two oxygen atoms, causing
us to predict that the acetal or ketal is not stable, the acetal or ketal can be isolated if the water
eliminated from the hemiacetal (or hemiketal) is removed from the reaction mixture. This is
because, if water is not available, the only compound the acetal or ketal can form is an O-
methylated carbonyl compound, which is less stable than the acetal or ketal.
The acetal or ketal can be transformed back to the aldehyde or ketone in an acidic aqueous
solution.

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Activity: Write the reaction mechanism for Hemiacetal and hemiketal formation and why is
protonation of the carbonyl oxygen needed?
3.1.3 Cyanohydrins
Hydrogen cyanide adds to aldehydes and ketones to form cyanohydrins. This reaction forms a
product with one more carbon atom than the reactant. In the first step of the reaction, the cyanide
ion attacks the carbonyl carbon. The alkoxide ion then accepts a proton from an undissociated
molecule of hydrogen cyanide.

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Because hydrogen cyanide is a toxic gas, the best way to carry out this reaction is to generate
hydrogen cyanide during the reaction by adding HCl to a mixture of the aldehyde or ketone and
excess sodium cyanide. Excess sodium cyanide is used in order to make sure that some cyanide
ion is available to act as a nucleophile.
In basic solutions, since oxygen is coming to be negatively charged having lost its proton and
cyanohydrin is converted back to the carbonyl compound. The addition of hydrogen cyanide to
aldehydes and ketones is a synthetically useful reaction because of the subsequent reactions that
can be carried out on the cyanohydrin.

3.1.4. Carbinolamines
Carbinolamine are neutral tetrahedral intermediate (unstable) formed when primary amines,
reacts with aldehydes or ketones in the presence of catalytic amount of acid and can exist in
equilibrium with two protonated forms. Protonation can take place on either the nitrogen or
the oxygen atom. Elimination of water from the oxygen-protonated intermediate forms a
protonated imine that loses a proton to yield the imine.

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 Mechanism for imine formation

The equilibrium favors the nitrogen-protonated tetrahedral intermediate because nitrogen is more
basic than oxygen. The equilibrium can be forced toward the imine by removing water as it is
formed or by precipitation of the imine product. Overall, the addition of a nitrogen nucleophile to
an aldehyde or a ketone is a nucleophilic addition–elimination reaction: nucleophilic addition of
an amine to form an unstable tetrahedral intermediate, followed by elimination of water. The
tetrahedral intermediates are unstable because the newly formed sp3 carbon is bonded to an
oxygen and to a nitrogen which is another electronegative atom. Water is eliminated, and loss of a
proton from the resulting protonated imine forms a stable imine.
3.1.5 Addition of Grignard Reagents
Attack of a Grignard reagent on a carbonyl carbon forms an alkoxide ion that is complexed with
magnesium ion. Addition of water or dilute acid breaks up the complex. Then alcohol is obtained.
When a Grignard reagent reacts with formaldehyde (H2C=O), the addition product is a primary
alcohol.

When a Grignard reagent reacts with an aldehyde other than formaldehyde, the addition
product is a secondary alcohol.

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Page 59
When a Grignard reagent reacts with a ketone, the addition product is a tertiary alcohol.

In the following reactions, numbers are used with the reagents to indicate that the acid is not added
until the reaction with the Grignard reagent is complete:

A Grignard reagent can also react with carbon dioxide. The product of the reaction is a
carboxylic acid with one more carbon atom than the Grignard reagent has.

In addition to reacting with aldehydes and ketones which are Class II carbonyl compounds,
Grignard reagents react with Class I carbonyl compounds which have groups that can be
replaced by another group.

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 Activity
1. How you might prepare the following alcohols from aldehyde and ketones?
H
CH2CH2OH
a) OH

b)

3.1.6 Addition of Hydrogen

 Aldehydes and ketones can be reduced to alcohols by molecular Hydrogen in the presence of
metal catalysts such as Pt, Pa or Ni.

3.1.7. Hydride Additions (lithium-aluminum hydride and sodium-borohydride

Addition of hydride ion to an aldehyde or ketone forms an alkoxide ion. Subsequent
protonation by an acid produces an alcohol. The overall reaction adds H2 to the carbonyl
group. Recall that the addition of hydrogen to an organic compound is a reduction reaction.
Lithium aluminium hydride (LiAlH4) or sodium borohydride (NaBH4) can used as the source

of hydride ion. A simplified view of the mechanism involves the formation of an intermediate
alkoxide, which on protonation yields a primary or secondary alcohol. Aldehydes and ketones
are generally reduced using sodium borohydride (NaBH4) as the source of hydride ion.
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Aldehydes other than formaldehyde are reduced to primary alcohols, and ketones are reduced
to secondary alcohols. Notice that the acid is not added to the reaction mixture until the
reaction with the hydride donor is complete.

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The reaction of a Class I carbonyl compound (i.e., a carbonyl compound with a group that can be
replaced by another group) with hydride ion involves two successive reactions with the
nucleophile. (Recall that Class I carbonyl compounds also undergo two successive reactions with a
Grignard reagent). Sodium borohydride (NaBH 4) is not a sufficiently strong hydride donor to react
with the less reactive (compared with aldehydes and ketones) esters, carboxylic acids, and amides,
so esters, carboxylic acids, and amides must be reduced with lithium aluminum hydride (LiAlH4),
a more reactive hydride donor. Because lithium aluminum hydride is more reactive than sodium
borohydride, it is not as safe or as easy to use. Since it reacts violently with protic solvents, lithium
aluminum hydride must be used in a dry, aprotic solvent. The reaction of an ester with LiAlH4
produces two alcohols, one corresponding to the acyl portion of the ester and one corresponding to
the alkyl portion.
Explain why lithium aluminum hydride is more reactive than sodium borohydride.
When an ester reacts with hydride ion, the first reaction is a nucleophilic acyl substitution reaction
because an ester has a group that can be substituted by hydride ion. The product of this reaction is
an aldehyde. The aldehyde then undergoes a nucleophilic addition reaction with a second
equivalent of hydride ion, forming an alkoxide ion, which when protonated gives a primary
alcohol. The reaction cannot be stopped at the aldehyde stage because an aldehyde is more
reactive than an ester toward nucleophilic attack.

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 Mechanism for the reaction of an ester with hydride ion

3.2. Addition-Elimination Reactions

All the addition-elimination reactions covered here involve nucleophilic attack on a carbonyl carbon
(C=O), followed by elimination.
3.2.1. Imines and Related Compounds
Aldehydes and ketones react with primary amines (RNH 2) to yield imines and react with
secondary amines (R2NH) to form enamines. An enamine is α, β-unsaturated tertiary amine with
a double bond in the α, β - position relative to the nitrogen atom. Notice that the double bond is in
the part of the molecule that comes from the aldehyde or ketone. The name ―enamine comes
from ―ene + ―amine with the ―e omitted in order to avoid two successive vowels.

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  Secondary amines add to aldehydes and ketones to form Carbinolamines, but their
carbinolamine intermediates can dehydrate to a stable product only in the direction that leads to
a carbon–carbon double bond:

3.2.2. Wittig Reaction

An aldehyde or a ketone reacts with a phosphonium ylide (pronounced ―ILL-id) to form an
alkene. An ylide is a compound that has opposite charges on adjacent covalently bonded atoms
with complete octets. The ylide can also be written in the double bonded form because phosphorus
can have more than eight valence electrons.

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The reaction of an aldehyde or a ketone with a phosphonium ylide to form an alkene is called a Wittig
reaction. The overall reaction amounts to interchanging the double-bonded oxygen of the carbonyl
compound and the double-bonded carbon group of the phosphonium ylide.

Evidence has accumulated that the Wittig reaction is a concerted [2 + 2] cycloaddition reaction,
the first step in the reaction mechanism involves nucleophilic attack by the carbon atom of the
triphenyphosphonium methylide. It is called a [2 + 2] cycloaddition reaction because, of the four π
electrons involved in the cyclic transition state, two come from the carbonyl group and two come
from the ylide. The driving force for the reaction is the formation of the very strong bond in
triphenylphosphine oxide. Elimination of triphenylphosphine oxide forms the alkene product.

Example

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The phosphonium ylide needed for a particular synthesis is obtained by an SN2 reaction between
triphenylphosphine and an alkyl halide with the appropriate number of carbon atoms. A proton
on the carbon adjacent to the positively charged phosphorus atom is sufficiently acidic (pKa = 35)
to be removed by a strong base such as butyllithium.

If two sets of reagents are available for the synthesis of an alkene, it is better to use the one that
requires the less sterically hindered alkyl halide for synthesis of the ylide. Recall that the more
sterically hindered the alkyl halide, the less reactive it is in an SN2 reaction.
Example:

The Wittig reaction is a very powerful way to make an alkene because the reaction is completely
regioselective—the double bond will be in only one place.

The Wittig reaction also is the best way to make a terminal alkene such as
methylenecyclohexane because other methods would form a terminal alkene only as a minor
product.

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 3.2.3. Acetals
 Hemiacetals can undergo further reaction, with a second equivalent of alcohol, to yield an
acetal.

 Reaction of a ketone with excess alcohol also forms a ketal.

3.2.4. Ester hydrolysis and formation

Hydrolysis is a chemical process in which a certain molecule is split into two parts by the addition of a
molecule of water. One fragment of the parent molecule gains a hydrogen ion; other group collects the
remaining hydroxyl group. This reaction is reverse of ester synthesis from corresponding carboxylic
acid and alcohol.

The mechanism of acid-catalyzed ester hydrolysis

Steps 1 through 3 show the formation of the tetrahedral intermediate. Dissociation of the tetrahedral

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intermediate is shown in steps 4 through 6.
Step 1: Protonation of the carbonyl oxygen of the ester

Step 2: Nucleophilic addition of water to protonated form of ester

Step 3: Deprotonation of the oxonium ion to give the neutral form of the tetrahedral intermediate

Step 4: Protonation of the tetrahedral intermediate at its alkoxy oxygen.

Step 5: Dissociation of the protonated form of the tetrahedral intermediate to an alcohol and the
protonated form of the carboxylic acid.

Step 6: Deprotonation of the protonated carboxylic acid

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Protonation of the carbonyl oxygen, as emphasized earlier, makes the carbonyl group more
susceptible to nucleophilic attack.

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3.2.5. Reactions of Acid Chlorides
Acid chlorides are very reactive towards Nucleophilic substitution and can be converted into a variety
of compounds, including less reactive carboxylic acid derivatives. In all cases, nucleophilic acyl
substitution leads to the introduction of a nucleophile at the expense of chlorine. Reaction with
reducing agents or organometallic compounds can lead to the formation of intermediate aldehydes or
ketones.

Conversion of acyl chlorides to other carboxylic acid derivatives reaction with carboxylic
acids
Acyl chlorides react with carboxylic acids to yield acid anhydrides. When this reaction is used for
preparative purposes, a weak organic base such as pyridine is normally added. Pyridine is a
catalyst for the reaction and also acts as a base to neutralize the hydrogen chloride that is formed.

Reaction with alcohols: Acyl chlorides react with alcohols to form esters. The reaction is
typically carried out in the presence of pyridine.

Reaction with ammonia and amines: Acyl chlorides react with ammonia and amines to form
amides. A base such as sodium hydroxide is normally added to react with the hydrogen chloride
produced.
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Hydrolysis: Acyl chlorides react with water to yield carboxylic acids. In base, the acid is
converted to its carboxylate salt. The reaction has little preparative value because the acyl chloride
is chloride nearly always prepared from the carboxylic acid rather than vice versa.

If you see the mechanism of hydrolysis, the tetrahedral intermediate has three potential leaving
groups on carbon: two hydroxyl groups and a chlorine. In the second stage of the reaction, the
tetrahedral intermediate dissociates, restoring the resonance-stabilized carbonyl group. Loss of
chloride from the tetrahedral intermediate is faster than loss of hydroxide; chloride is less basic
than hydroxide and is a better leaving group.
First stage: Formation of the tetrahedral intermediate by nucleophilic addition of water to the
carbonyl group.

Second stage: Dissociation of the tetrahedral intermediate by dehydrohalogenation.

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3.2.6. Reactions of Acid Anhydrides
Acid anhydrides undergo reactions similar to acid chlorides. These reactions involve the
substitution of a carboxylate group (RCO 2-). Nucleophilic acyl substitution in acid anhydrides
involves cleavage of a bond between oxygen and one of the carbonyl groups. One acyl group is
transferred to an attacking nucleophile; the other retains its single bond to oxygen and becomes the
acyl group of a carboxylic acid.
Reduction using LiAlH4 can produce an intermediate aldehyde and carboxylate, which are
subsequently reduced to alcohols.

One reaction of this type, Friedel-Crafts acylation is already familiar to us.

3.2.7. Hydrolysis of Amides

Amides are very unreactive compounds, which is comforting, since proteins are composed of
amino acids linked together by amide bonds. Amides do not react with halide ions, carboxylate
ions, alcohols, or water because, in each case, the incoming nucleophile is a weaker base than the
leaving group of the amide. But, the amide bond is cleaved on heating in the presence of strong
acids or bases. Nominally, this cleavage produces an amine and a carboxylic acid.

When an amide is hydrolyzed under acidic conditions, the acid protonates the carbonyl oxygen
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and increases the susceptibility of the carbonyl carbon to nucleophilic attack. Nucleophilic attack
by water on the carbonyl carbon leads to tetrahedral intermediate I, which is in equilibrium with
its nonprotonated form, tetrahedral intermediate II. Reprotonation can occur either on oxygen to
reform tetrahedral intermediate I or on nitrogen to form tetrahedral intermediate III. Protonation
on nitrogen is favored because the NH2 group is a stronger base than the OH group.
Mechanism for acid-catalyzed hydrolysis of an amide

Why an amide cannot be hydrolyzed without a catalyst? In the uncatalyzed reaction, the
amide is not protonated. Therefore, water, a very poor nucleophile, must attack a neutral
amide that is much less susceptible to nucleophilic attack than a protonated amide would be

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3.2.8. Reductions of Acid Derivatives (Ester and Amide etc)
We have just seen that there are two steps in a nucleophilic acyl substitution reaction: formation
of a tetrahedral intermediate and collapse of the tetrahedral intermediate. The weaker the
base attached to the acyl group, the easier it is for both steps of the reaction to take place. In other
words, the reactivity of a carboxylic acid derivative depends on the basicity of the substituent
attached to the acyl group: The less basic the substituent, the more reactive the carboxylic acid
derivative.
Relative basicities of the leaving groups

Relative reactivities of carboxylic acid derivatives

Where shall aldehydes and ketones be?

How does having a weak base attached to the acyl group make the first step of the nucleophilic
substitution reaction easier? First of all, a weaker base is a more electronegative base; that is, it is
better able to accommodate its negative charge. Thus, weaker bases are better at withdrawing
electrons inductively from the carbonyl carbon; electron withdrawal increases the carbonyl
carbon’s susceptibility to nucleophilic attack.

Esters and amides are reduced to primary alcohols and amines, respectively. Reduction of primary
amides yields primary amines, while secondary and tertiary amides can be reduced to secondary and
tertiary amines, respectively.

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3.3 Enolization-Ketonization reactions
It is obvious that hydrogen on a carbon adjacent to a carbonyl carbon is somewhat acidic, we can
understand why keto and enol tautomers interconvert. Keto–enol interconversion is also called keto–
enol tautomerization or enolization. The inter-conversion of the tautomers can be catalyzed by either
acids or bases.
In a basic solution, hydroxide ion removes a proton from the α-carbon of the keto tautomer. The
anion that is formed has two resonance contributors: a carbanion and an enolate ion. The enolate
ion contributes more to the resonance hybrid because the negative charge is better accommodated
by oxygen than by carbon. Protonation on oxygen forms the enol tautomer, whereas protonation
on the α-carbon reforms the keto tautomer.
Base-catalyzed keto–enol interconversion

In an acidic solution, the carbonyl oxygen of the keto tautomer is protonated and water removes a
proton from the α-carbon forming the enol.

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Acid-catalyzed keto–enol inter-conversion

Notice that the steps are reversed in the base and acid-catalyzed reactions. In the base- catalyzed
reaction, the base removes the α-proton in the first step and the oxygen is protonated in the
second step. In the acid-catalyzed reaction, the acid protonates the oxygen in the first step and the
α-proton is removed in the second step. Notice also how the catalyst is regenerated in both the
acid- and base-catalyzed mechanisms. The carbon–carbon double bond of an enol suggests that
it is a nucleophile like an alkene. An enol is more electron rich than an alkene because the oxygen
atom donates electrons by resonance. An enol, therefore, is a better nucleophile than an alkene.

Carbonyl compounds that form enols undergo substitution reactions at the α-carbon. When an α-
substitution reaction takes place under acidic conditions, water removes a proton from the α-
carbon of the protonated carbonyl compound. The nucleophilic enol then reacts with an
electrophile. The overall reaction is an α-substitution reaction in which one electrophile (E+) is
substituted for another (H+).
Mechanisms
Acid-catalyzed α-substitution reaction

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Base-catalyzed α-substitution reaction

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3.3.1. Haloform Reaction of Methyl Ketones
In the presence of excess base (hydroxide) and excess halogen ( chlorine, bromine or iodine), a methyl ketone
is first converted into a trihalo-substituted ketone. Then hydroxide ion attacks the carbonyl carbon of the trihalo-
substituted ketone. Because the trihalomethyl ion is a weaker base than hydroxide ion, the trihalomethyl ion is
the group more easily expelled from the tetrahedral intermediate, so the final product is a carboxylic acid. The
conversion of a methyl ketone to a carboxylic acid is called a haloform reaction because one of the products is
haloform— CHCl3 (chloroform), CHBr3 (bromoform), or CHI3 (iodoform)
3.3.2. Alkylation at the α-Carbon

Alkylation of the α-carbon of a carbonyl compound is an important reaction because it gives us another
way to form a carbon–carbon bond. Alkylation occurs when the nucleophilic enolate ion reacts with the
electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by back-side attack. These
reactions produce new carbon–carbon bonds.
O
O
C SN2 C
C X C + X
C + reaction C

Enolate ion Alkyl halide

3.3.3. Aldol and Related Condensation Reactions
Aldol condensation
Aldehydes and ketones are electrophiles and therefore react with nucleophiles. When a proton is
removed from the α-carbon of an aldehyde or a ketone, the resulting anion is a nucleophile and
therefore reacts with electrophiles. An aldol addition is a reaction in which both of these activities
are observed: One molecule of a carbonyl compound after a proton is removed from an α-carbon
reacts as a nucleophile and attacks the electrophilic carbonyl carbon of a second molecule of the

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carbonyl compound. An aldol addition is a reaction between two molecules of an aldehyde or two
molecules of a ketone. When the reactant is an aldehyde, the addition product is a β-
hydroxyaldehyde that is why the reaction is called an aldol addition (―ald for aldehyde,
―ol for alcohol). When the reactant is a ketone, the addition product is a β-hydroxyketone,
because the addition reaction is reversible, good yields of the addition product are obtained only if
it is removed from the solution as it is formed.
In the first step of an aldol addition, a base removes an α-proton from the carbonyl compound,
creating an enolate. The enolate adds to the carbonyl carbon of a second molecule of the carbonyl
compound, and the resulting negatively charged oxygen is protonated by the solvent.
Mechanism for the aldol addition

Ketones are less susceptible than aldehydes to attack by nucleophiles, so aldol additions occur
more slowly with ketones. The relatively high reactivity of aldehydes in competing aldol addition
reactions is what causes them to give low yields of α-alkylation products,

Because an aldol addition reaction occurs between two molecules of the same carbonyl
compound, the product has twice as many carbons as the reacting aldehyde or ketone.
Dehydration of the Aldol Product:
The β -hydroxy aldehyde products of aldol addition undergo dehydration on heating, to yield a stable
α , β -unsaturated Aldehydes. Loses the elements of H 𝟐O from the α and β carbons to form an α , β -
unsaturated carbonyl compound.

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Mixed Aldol Addition
If two different carbonyl compounds are used in an aldol addition, four products can be formed
because each enolate can react both with another molecule of the carbonyl compound from which
the enolate was formed and with the other carbonyl compound. In the following example, both
carbonyl compound A and carbonyl compound
;
B can lose a proton from an α- carbon to form
enolates A- and B- A- can react with either A or B, and can react with either A or B:

The four products have similar physical properties, making them difficult to separate.
Consequently, a mixed aldol addition that forms four products is not a synthetically useful
reaction.
How many possible products can be formed if one of the carbonyl compound has no an α-
hydrogen? Which one will be major?
The Claisen Condensation
When two molecules of an ester undergo a condensation reaction, the reaction is called a
Claisen condensation. The product of a Claisen condensation β-keto ester.
Example:

As in an aldol addition, in a Claisen condensation one molecule of carbonyl compound is

converted into an enolate when an α-hydrogen is removed by a strong base. The enolate attacks
the carbonyl carbon of a second molecule of ester. The base employed corresponds to the leaving
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group of the ester so that the reactant is not changed if the base acts as a nucleophile and attacks
the carbonyl group

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After nucleophilic attack, the Claisen condensation and the aldol addition differ. In the Claisen
condensation, the negatively charged oxygen reforms the carbon–oxygen π bond and expels the --
OR group. In the aldol addition, the negatively charged oxygen obtains a proton from the solvent.
Thus, the Claisen condensation is a substitution reaction, whereas the aldol addition is an addition

reaction.
Give the products of the following reactions:

Mixed Claisen Condensation: A mixed Claisen condensation is a condensation reaction

between two different esters. Like a mixed aldol addition, a mixed Claisen condensation is a
useful reaction only if it is carried out under conditions that foster the formation of primarily one
product. Otherwise, a mixture of products that are difficult to separate will be formed.
Mannich condensation: The condensations of imines with aldehydes or ketones in a manner
similar aldol condensation.

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 4. OXIDATION–REDUCTION REACTIONS
Many of the organic reactions can be classified as either oxidation or reductions. Simple way to
identify a given reaction whether it is oxidation or reduction is oxidation count. It is the number
of π-bond, cyclic system and bonds with the hetero atoms like oxygen, nitrogen, halogens etc.
Comparing the result of oxidation count of reactants and products, if the oxidation count of the
product is greater than that of the product then we can conclude as the reaction to be oxidation.
The reverse will be reduction reaction.
An oxidation is a reaction that results in a loss of electron density by carbon. Oxidation is loss of
hydrogen and gaining of oxygen. This loss is usually caused either by bond formation between carbon
a more electronegative atom (usually oxygen, nitrogen or a halogen) or by bond breaking between
carbon and a less electroactive atom (hydrogen). Oxidation decreases electron density on carbon by:
Forming one of these: C-O, C-N, C-X, or breaking this: C-H whereas, A reduction is a reaction that
results in a gain of electron density by carbon. Reduction is loss of oxygen, gaining of hydrogen and
loss of heteroatom such O, N, and halogens. This gain is usually caused either by bond formation
between carbon and a less electronegative atom or by bond breaking between carbon and a more
electronegative atom.
Reduction increases electron density on carbon by: Forming this: C-H or breaking one of these: C-O,
C-N and C-X
Examples: Oxidation count of some organic compounds

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 4.1. Oxidation reactions
Oxidations of almost all organic compounds involves either introductions of a heteroatom (mostly
O atom) or losing hydrogen atoms.
4.1.1. Oxidation of alcohols
One of the most valuable reactions of alcohols is their oxidation to yield carbonyl compounds- the
opposite of the reduction of a carbonyl compound to yield an alcohol.

Primary alcohols may be oxidized either to an aldehyde or to a carboxylic acid whereas secondary
alcohols are oxidized to ketones. A reagent that is often used to oxidize alcohols is KMnO 4, chromic
trioxide (CrO3) or chromate (CrO42-) or dichromate (Cr2O72-) up on acidification, which reagent is used
in a specific case depends on such factors as cost, convenience, reaction yield and alcohol sensitivity.
These reactions are easily recognized as oxidations because the number of C-H bonds in the reactant
decreases and the number of C-O bonds increases.

Primary alcohols are initially oxidized to aldehydes by these reagents. The reaction, however, does
not stop at the aldehyde. Instead, the aldehyde is further oxidized to a carboxylic acid.

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 The oxidation of primary or secondary alcohol involves the removal of hydrogen from the carbon
to which the OH is attached. The carbon bearing the OH group in a tertiary alcohol is not bonded to
hydrogen, so the OH group cannot be oxidized to a carbonyl group.

Mechanism for alcohol oxidation by chromic acid

4.1.2. Oxidation of aldehyde and ketone

Aldehydes are oxidized to carboxylic acids. Because aldehydes are generally easier to oxidize than
primary alcohols, any of the reagents used for oxidizing primary alcohols to carboxylic acids can be
used to oxidize aldehydes to carboxylic acids.

Silver oxide is a mild oxidizing agent. A dilute solution of silver oxide in aqueous ammonia
(Tollen‘s reagent) will oxidize an aldehyde, but it is too weak to oxidize an alcohol or any
other functional groups. An advantage to using Tollen‘s reagent to oxidize an aldehyde is that
reaction occurs under basic conditions. Therefore, you do not have to worry about harming
other functional groups in the molecule that may undergo a reaction in an acidic solution.

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Ketones: do not react with most of the reagents used to oxidize aldehydes.

However, both aldehydes and ketones can be oxidized by a peroxyacid. Aldehydes are oxidized to
carboxylic acids and ketones are oxidized to esters. A peroxyacid (also called a per-carboxylic acid or
an acyl hydroperoxide) contains one more oxygen than carboxylic acids, and it is this oxygen that is
inserted between the carbonyl carbon and the H of an aldehyde or the R of a ketone. The reaction is
called Baeyer-Villiger oxidation

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Activity
Give the products of the following reactions:

4.1.3. Oxidation of Multiple Bonds (olefins)

The pi system of C-C double bond is readily accessible to a variety of oxidizing agents such as
ozone, per acid, KMnO4, OsO4 (Osmium tetroxide) and etc.

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 Oxidation of Alkenes with Peroxyacids
Mechanism for epoxidation of an alkene

The addition of oxygen to an alkene is a stereospecific reaction. Because the reaction is

concerted, the C-C bond cannot rotate, so there is no opportunity for the relative positions of
the groups bonded to the sp2 carbons of the alkene to change. Therefore, a cis alkene forms a
cis epoxide. Similarly, a trans alkene forms a trans epoxide.
Increasing the electron density of the double bond increases the rate of epoxidation because it
makes the double bond more nucleophilic. Alkyl substituents increase the electron density of
the double bond.
Ozonolysis
When an alkene is treated with ozone at low temperatures, the double bond breaks and the
carbons that were doubly bonded to each other find themselves doubly bonded to oxygens
instead. This oxidation reaction is known as ozonolysis.

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 The product of ozone addition to an alkene is a molozonide. (The name molozonide
indicates that one mole of ozone has added to the alkene.) The molozonide is unstable
because it has two O-O bonds; it immediately rearranges to a more stable ozonide.

Ozonides are explosive, so they are seldom isolated. In solution, they are easily cleaved to
carbonyl compounds. If the ozonide is cleaved in the presence of a reducing agent such as
zinc or dimethyl sulfide, the products will be ketones and/or aldehydes.
The reducing agent prevents aldehydes from being oxidized to carboxylic acids. Cleaving the
ozonide in the presence of zinc or dimethyl sulfide is referred to as ―working up the
ozonide under reducing conditions.

Cleavage in the presence of H2O2 is referred to as ―working up the ozonide under oxidizing
conditions.
Hydroxylation of Alkenes
An alkene can be oxidized to a 1, 2-diol either by potassium permanganate (KMnO 4) in a cold
basic solution or by osmium tetroxide (OsO 4). The solution of potassium permanganate must

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 be basic, and the oxidation must be carried out at room temperature or below. If the solution is
heated or if it is acidic, the diol will be oxidized further. A diol is also called a glycol. The OH
groups are on adjacent carbons in 1, 2-diols, so 1, 2-diols are also known as vicinal diols or
vicinal glycols.
Both KMnO4 and OsO4 form a cyclic intermediate when they react with an alkene. The
reactions occur because manganese and osmium are in a highly positive oxidation state and,
therefore, attract electrons. Formation of the cyclic intermediate is a syn addition because both
oxygens are delivered to the same side of the double bond. Therefore, the oxidation reaction is
stereospecific—a cis cycloalkene forms only a cis diol.
Mechanism for cis glycol formation

Unlike permanganate, cyclic osmate intermediate is hydrolyzed with hydrogen peroxide that
reoxidizes osmium to osmium tetroxide. Higher yields of the diol are obtained with osmium
tetroxide because the cyclic osmate intermediate is less likely to undergo side reactions
4.2. Reduction reactions
Reduction reactions usually involves gaining hydrogen and, in many cases, losing a heteroatom
(such as O, N & halogen). An organic compound is reduced when hydrogen (H 2) is added to it. A
molecule of H2 can be thought of as being composed of (1) two hydrogen atoms, (2) two electrons
and two protons, or (3) a hydride ion and a proton.

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 Organic Chemistry II Chem2041 2022

4.2.1. Catalytic Hydrogenation or Reduction by addition of two hydrogen atoms

Hydrogen atom can be added to the site of unsaturated (carbon-carbon double or triple bonds)
in the presence of a transitional metal catalyst. These reactions, called catalytic
hydrogenations, are reduction reactions because there more C- H bonds in the products than
the reactants. Alkenes and alkynes are both reduced to alkanes.

In a catalytic hydrogenation, the H-H bond breaks homolytically. This means that the
reduction reaction involves the addition of two hydrogen atoms to the organic molecules.
Only the alkene substitute is reduced in the following reaction. The very stable benzene ring
can be reduced only under special conditions.

The carbonyl group of ketones and aldehydes can be reduced by catalytic hydrogenation,
with Raney nickel as a metal catalyst. (Raney nickel is finely dispersed nickel with adsorbed
hydrogen, so an external source of H 2 is not needed.) Aldehydes are reduced to primary
alcohols, and ketones are reduced to secondary alcohols.

The carbonyl groups of carboxylic acids, esters and amides are less reactive, so they are
harder to reduce than the carbonyl groups of aldehydes and ketones. They cannot reduce by
catalytic hydrogenation (except under extreme conditions).

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Activity
Give the products of the following reactions:

4.2.2. Hydride reduction

Carbonyl groups are easily reduced by metal hydrides such as sodium borohydride (NaBH 4)
or lithium aluminium hydride (LiAlH4). The actual reducing agent in metal hydride
reductions is hydride ion (H-).hydride ion adds to the carbonyl carbon, and the alkoxide ion
that is formed is subsequently protonated. In other words, the carbonyl group is reduced by
adding an H- followed by an H+. The mechanisms for reduction by these reagents are:

Or

Aldehydes, ketones and acyl halides can be reduced by sodium borohydride

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The metal-hydrogen bonds in Lithium aluminium hydride are more polar than the metal
hydrogen bonds in sodium borohydride. As a result, LiAlH 4 is a stronger reducing agent than
NaBH4. Consequently, both LiAlH4 and NaBH4 reduce aldehydes, ketones, and acyl
aldehydes, but LiAlH4 is not generally used to reduce only compounds- such as carboxylic
acids, esters, and amides-that cannot be reduced by the milder reagent.

A chemoselective reaction is a reaction in which a reagent reacts with one functional group
in preference to another. For example, NaBH4 in isopropyl alcohol reduces aldehydes faster
than it reduces ketones.

4.2.3. Dissolving metal reduction

When a compound is reduced using sodium in liquid ammonia, sodium donates an electron to
the compound and ammonia donates a proton. This sequence is repeated, so the overall
reaction of adds two electrons and two protons to the compound. Such a reaction is called
dissolving metal reduction. The mechanism for dissolved-metal reduction that converts an
alkynes to a trans alkene.

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Mechanism

Sodium or (lithium) in liquid ammonia cannot reduce a carbon-carbon double bond. This
makes it a useful reagent for reducing a triple bond in a compound that also contains a double
bond.

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5. INTRODUCTION TO CHEMISTRY OF BIOMOLECULES

Compounds are either inorganic compounds or organic compounds. Inorganic compounds are
relatively small, simple molecules that usually lack C (a few may have one C atom).
Examples: CO2, NH3, H2O, O2, H2. Whereas, organic compounds are Larger, more complex
molecules whose structure is based on a backbone of C atoms (always contain C as a major
part of their structure). Examples: C6H12O6, C2H5COOH.
Biomolecules are naturally occurring organic compounds which form the basis of life, i.e.,
they build up the living system and responsible for their growth and maintenance.
Living systems are mainly made up of biomolecules like
Carbohydrates
Lipids (fats)
Proteins
Nucleic acid (DNA and RNA)
They are known as primary metabolites. These are large molecules (polymer) that are made
up of smaller building blocks (monomers) Proteins and carbohydrates are essential
constituents of our food. These biomolecules interact with each other and constitute the
molecular logic of life processes. In addition, some simple molecules like vitamins and
mineral salts also play an important role in the functions of organisms.
5.1. Carbohydrate
It is the most abundant class of compounds in the biological world, making up more than
50% of the dry weight of the Earth‘s biomass. Carbohydrates are primarily produced by
plants and form a very large group of naturally occurring organic compounds. Some common
examples of carbohydrates are cane sugar, glucose, starch, etc. Carbohydrates are important
constituents of all living organisms and have a variety of different functions. Some are
important structural components of cells; others act as recognition sites on cell surfaces.
Other carbohydrates serve as a major source of metabolic energy. Almost all carbohydrates
are chiral and optically active. Early chemists noted that carbohydrates have molecular
formulas that make them appear to be hydrates of carbon, Cn (H 2O) n hence the name. Many,
but not all, sugars have the empirical formula Cn (H2O) n.

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Carbohydrates are polyhydroxy aldehydes such as D-glucose, polyhydroxy ketones such as

D-fructose, and compounds such as sucrose that can be hydrolyzed to polyhydroxy aldehydes
or polyhydroxy ketones.
There are two classes of carbohydrates: simple carbohydrates and complex carbohydrates.
Simple carbohydrates are monosaccharaides (single sugars) which cannot be hydrolyzed
into smaller molecules. Monosaccharides bearing an aldehyde are known as aldoses, whereas
those bearing a ketone are known as ketoses. Sugars bearing three, four, five and six carbon
atoms are known as trioses, tetroses, pentoses and hexoses, respectively.
Complex carbohydrates contain two or more sugar subunits linked together by oxygen
bridges. These can be hydrolyzed to their component sugars (e.g. sucrose is a disaccharide
which can be hydrolyzed to one glucose molecule and one fructose molecule, while cellulose
is a polysaccharide which can be hydrolyzed to give around 3000 glucose molecules).
Carbohydrates are most often drawn as Fischer projections. Emil Fischer and his colleagues
studied carbohydrates in the late nineteenth century, when techniques for determining the
configurations of compounds were not available. Fischer arbitrarily assigned the R-
configuration to the dextrorotatory isomer of glyceraldehyde that we call D-glyceraldehyde.
It was correct that D-Glyceraldehyde is (R)-(+)-glyceraldehyde, and L-glyceraldehyde is
(S)-(-)-glyceraldehyde. In the projections the horizontal lines come out of the page, while the
vertical lines go into the page.

5.1.1. Glucose
The most abundant carbohydrate in nature is glucose. Living cells oxidize glucose in the first
of a series of processes that provide them with energy. When animals have more glucose than
they need for energy, they convert excess glucose into a polymer called glycogen. Animals
obtain glucose from food such as plants that contains glucose. Plants produce glucose by
photosynthesis. Because photosynthesis is the reverse of the process used by organisms to
obtain energy the oxidation of glucose to carbon dioxide and water plants require energy to
carry out photosynthesis. Plants obtain the energy they need for photosynthesis from sunlight,
captured by chlorophyll molecules in green plants.

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Glucose occurs in most sweet fruits and in honey. Ripe grapes contain as much as 20-30 per cent
of glucose, hence its name grape sugar. In small amounts it is a normal constituent of human
blood and urine. The urine of diabetic persons may contain glucose to the extent 8-10 per cent. In
the combined form it occurs in cane sugar and other polysaccharides. Glucose is a colourless
crystalline solid, m.p. 146°c. The monohydrate which crystallises from cold water melts at 86°c.
It is very soluble in water (84 g. per l00 g) but sparingly soluble in alcohol, and insoluble in
ether. It is approximately three to fourths as sweet as cane sugar. Naturally occurring glucose is
optically active and its solution is dextrorotatory (hence its name dextrose). Glucose is
synthesized in living organisms by breaking down the ingested carbohydrates through the process
of glycolysis within the cell. As a consequence of metabolizing glucose, the molecule is either
stored as glycogen in the body or used up as energy in the form of adenosine triphosphate (ATP).
The production of glycogen from glucose takes place through a process of glycogenesis. The
liberation of energy in the form of ATP happens by breaking down glucose through the process
of the citric acid cycle or fermentation.
5.1.2 The Structure and Configuration of Glucose
Glucose combine together multiple times with each other and other compounds to form a
polysaccharide. It is a six carbon compound and a hexose molecule because it has six carbon
atoms. The glucose molecule may be pictured as a linear chain, but there are different
structural forms of glucose. Glucose’s different structural forms mean it has different
rotations and confirmations.
The chemical molecular formula of the glucose molecule is C6H12O6. It contains an aldehyde
(-CHO) group present on the first carbon (C 1). Thus, it is an aldose type when the
monosaccharides are classified according to the nature of the functional group. The aldehyde
containing glucose can convert into a ketone containing fructose because they are isomers.
They have equal molecular formulas but differ in their structures and configurations.
The carbons in glucose molecules are connected by covalent bonds that release energy to an
organism when broken. The glucose molecule consists of 12 hydrogen and six oxygen atoms
attached to the parent carbon chain. In general, for ease of understanding, the glucose
molecule is drawn as a linear chain of 6 carbon atoms. But there are different structural forms
of glucose. This means that glucose changes the nature of its chain, its optical rotation, and its
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confirmations under different conditions. Glucose occurs mostly in the human body as a ring
shape that mimics a hexagon.
Different structural forms of glucose:
Fischer projection of glucose structure
It shows a two dimensional (2D) structure of a linear glucose chain.

The above structures show two different forms of glucose structure. The D-glucose is dextro
glucose, which has an optical rotation towards the right side, meaning it is dextrorotatory. The
dextro glucose structure turns plane-polarized light in a clockwise direction.
The L-glucose is levo glucose, which has an optical rotation towards the left side, meaning it is
levorotatory. The levo glucose twists plane-polarised light in an anti-clockwise direction. L and
D glucose are mirror images of each other. Since they are mirror images of each other, they are
called enantiomers. The levo form is the enantiomer of the dextro form of glucose.
Haworth projection of glucose structure which demonstrates a 3D structure of glucose molecules
in a hexagonal ring format.

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The hexagonal ring of glucose is formed by the interaction between the oxygen atom of the
aldehyde group at the C1 and C5 atoms of the molecule. The ring form of glucose is chemically
named glucopyranose as it has a pyranose ring. Based on the optical rotation of the cyclic
glucose, the molecule is termed dextro or levo glucose. Also, based on the direction of the
functional group, the glucose molecule is given prefixes as alpha or beta.
Chair conformation of glucose structure
It is the most accurate form to represent the structure of cyclohexane. It is also termed ‘boat
conformation’ due to the shape of the molecules. It clearly shows the positions and tilt of the
atoms in the glucose molecules.

The above structure shows the equatorial arrangement of the atoms, meaning the atoms are seen
in the equatorial plane (horizontally). When the atoms are seen in a vertical plane, the glucose
molecule is structured in the axial configuration.
5.1.3 Anomeric forms of Monosaccharides
When a pyranose or furanose ring closes, the hemiacetal carbon atom is converted from a
flat carbonyl group to an asymmetric carbon. Depending on which face of the (protonated)
carbonyl group is attacked, the hemiacetal –OH group can be directed either up or down.
These two orientations of the hemiacetal –OH group give diastereomeric products called
anomers, and the hemiacetal or acetal carbon atom is called the anomeric carbon atom.
The preference of certain substituents bonded to the anomeric carbon for the axial position
is called the anomeric effect. Ano is Greek for “upper”; thus, anomers differ in configuration
at the upper-most asymmetric carbon. The anomeric carbon is the only carbon in the
molecule that is bonded to two oxygen atoms. The anomer with the anomeric –OH group
down (axial) is called the anomer, and the one with the anomeric –OH group up
(equatorial) is called the β –anomer.

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In fructose, the α -anomer has the anomeric - OH group down, trans to the terminal – CH 2OH
group, while the β -anomer has it up, cis to the terminal –CH2OH group.

5.1.4 Glycosides
Glycosides are cyclic acetal form of sugars and the bond between the anomeric carbon and
the alkoxy oxygen is called a glycosidic bond. They are prepared by the acid-catalysed
reaction of an alcohol with a pyranose or furanose. Naming of glycosides is done by
replacing the “e” of the sugar with “ide”. Example, a glycoside of glucose is glucoside and if
pyranose or furanose name is used, the acetal is called pyranoside or furanoside. Both α - and
β -glycoside obtained from the reaction of a single anomer with an alcohol (Scheme below).

The reason for the formation of both glycosides is shown in Scheme below. The protonation
of the anomeric carbon –OH group followed by elimination of water gives a
planar sp2 hybridized oxocarbenium ion. This can react with alcohol from both faces to give
the β -glycoside and the α-glycoside.

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Reducing and Non-reducing Sugars

A sugar with an aldehyde, a ketone, a hemiacetal, or a hemiketal group is a reducing sugar.
A sugar without one of these groups is a non-reducing sugar. Because glycosides are acetals
(or ketals), they are not in equilibrium with the open chain aldehyde (or ketone) in neutral or
basic aqueous solutions. Because they are not in equilibrium with a compound with a
carbonyl group, they cannot be oxidized by reagents such as Ag + or Br2. Glycosides,
therefore, are nonreducing sugars—they cannot reduce Ag + or [Link] (or
hemiketals) are in equilibrium with the open-chain sugars in aqueous solution. So as long as a
sugar has an aldehyde, a ketone, a hemiacetal, or a hemiketal group, it is able to reduce an
oxidizing agent and therefore is classified as a reducing sugar. Without one of these groups, it
is a nonreducing sugar.
Reducing property
Monosaccharides act as the best reducing agents.
They readily reduce oxidizing agents such as ferric cyanide, H2O2 and cupric ion.
In such reactions, the sugar is oxidized at the carbonyl group and the oxidizing agent
becomes reduced.

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Glucose and other sugar capable of reducing certain compounds are called reducing
sugars. Glucose reduces Tollen‘s reagent, Fehling‘s reagent, Benedict‘s reagent etc.
At the same time glucose is oxidized to gluconic acid.

5.1.5 Disaccharides
Disaccharides are sugars containing two molecules of monosaccharides. Disaccharides are
formed by the condensation of two molecules of monosaccharides with the elimination of one
molecule of water. In disaccharides, monosaccharides are linked by the glycosidic bonds.
Biologically important disaccharides are sucrose, maltose and lactose.
Maltose
Maltose is composed of two glucose molecules combined by a- 1, 4 glycosidic linkage. It is
commonly called malt sugar. Malt from sprouting barley is the major source of maltose. It is
a rather sweet sugar and is highly soluble in water.

Lactose
Lactose is commonly called as milk sugar. It is present in the milk of mammals. However
lactose is found in the urine of pregnant and lactating women. It is less soluble in water and
less sweet than sucrose.
Lactose has a free potential aldehyde group in the glucose molecule, not involved in the
glycosidic linkage between glucose and galactose molecules. Whereas, the potential aldehyde
group of galactose molecule is blocked in the linkage. Because of the presence of free
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aldehyde group in the glucose molecule, lactose can reduce Fehling‘s solution and is
therefore a reducing sugar.

Sucrose
Sucrose is ordinary ―table sugar‖. It is also called as ―cane sugar‖ as it can be obtained from
sugar cane. It is widely distributed in sugar cane, beet root, pine apple, honey, carrot and ripe
fruits. Is composed of glucose and fructose through an α–(1, 2)–β-glycosidic bond.
Sucrose consists of one molecule of glucose and one molecule of fructose. The linkage
between these molecules is formed between the aldehyde group of glucose and the ketone
group of fructose. Unlike the other disaccharides that have been discussed, sucrose is not a
reducing sugar and does not exhibit mutarotation because the glycosidic bond is between the
anomeric carbon of glucose and the anomeric carbon of fructose. Sucrose, therefore, does not
have a hemiacetal or hemiketal group, so it is not in equilibrium with the readily oxidized
open-chain aldehyde or ketone form in aqueous solution. Thus, both the potential aldehyde
group of glucose and the ketone group of fructose are blocked in the linkage and sucrose has
no free reducing group. On account of this structural peculiarity sucrose is a non-reducing
sugar.

5.1.6 Polysaccharides
Polysaccharides contain as few as 10 or as many as several thousand monosaccharide units
joined together by glycosidic linkages. The molecular weight of the individual polysaccharide
chains is variable. The most common polysaccharides are starch and cellulose.
There are two groups of polysaccharides. 1. Homopolysaccharides 2. Heteropolysaccharides
Homopolysaccharides are composed of only one type of monosaccharides. On hydrolysis

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they yield only one type of monosaccharides. [Link], glycogen, cellulose etc. which yield
only glucose on hydrolysis.
Heteropolysaccharides are composed of a mixture of monosaccharides. On hydrolysis, they
yield a mixture of monosaccharides. Eg. Hyaluronic acid, Heparin, Mucopolysaccharides.
The most common polysaccharides are starch and cellulose
Starch
Starch is the major form of stored carbohydrate in plant cells. They are abundantly found in
root, stem, vegetables, fruits and cereals. Its structure is identical to glycogen, except for a
much lower degree of branching (about every 20–30 residues. Starch is the major component
of flour, potatoes, rice, beans, corn, and peas. Starch is a mixture of two different
polysaccharides: amylose (about 20%) and amylopectin (about 80%). Amylose is composed
of unbranched chains of D-glucose units joined by α-1, 4 glycosidic linkages.

Amylopectin is a branched polysaccharide. Like amylose, it is composed of chains of D

glucose units joined by α-1, 4 glycosidic linkages. Unlike amylose, however, amylopectin
also contains α-1, 6 glycosidic linkages. These linkages create the branches in the
polysaccharide. Amylopectin can contain up to 106 glucose units, making it one of the largest
molecules found in nature.

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Animals store their excess glucose in a polysaccharide known as glycogen. Glycogen has a
structure similar to that of amylopectin, but glycogen has more branches. The branch points
in glycogen occur about every 10 residues, whereas those in amylopectin occur about every
25 residues. The high degree of branching in glycogen has important physiological effects.
When the body needs energy, many individual glucose units can be simultaneously removed
from the ends of many branches.
Cellulose
Cellulose is the structural material of higher plants. Cotton, for example, is composed of
about 90% cellulose, and wood is about 50% cellulose. Like amylose, cellulose is composed
of unbranched chains of D-glucose units. Unlike amylose, however, the glucose units in
cellulose are joined by β-1, 4 glycosidic linkages rather than by α-1, 4-glycosidic linkages. α-
1, 4-glycosidic linkages are easier to hydrolyze than linkages because of the anomeric effect
that weakens the bond to the anomeric carbon.

All mammals have the enzyme that hydrolyzes the linkages that join glucose units, but they
do not have the enzyme that hydrolyzes linkages. As a result, mammals cannot obtain the
glucose they need by eating cellulose.

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5.2 Lipids
The word lipid comes from the Greek “lipos”, which means “fat”.
Lipids are organic compounds, found in living organisms that are soluble in nonpolar organic
solvents.
Biological molecules that are insoluble in aqueous solutions and soluble in organic solvents
are classified as lipids. The lipids of physiological importance for humans have four major
functions:
They serve as structural components of biological membranes.
They provide energy reserves, predominantly in the form of triacylglycerols.
Both lipids and lipid derivatives serve as vitamins and hormones.
Lipophilic bile acids aid in lipid solubilization.
5.2.1 Fatty Acids
A fatty acid is a molecule characterized by the presence of a carboxyl group attached to a
long hydrocarbon chain. The fatty acids most frequently found in nature. The numbering of
carbons in fatty acids begins with the carbon of the carboxylate group.
Fatty acids may be divided into
saturated fatty acids and
unsaturated fatty acid
Saturated fatty acids
These are fatty acids which do not contain carbon-carbon double bonds. They have general
formula CnH2n+1 COOH. Saturated fatty acids commonly found in natural fats.
C13H27COOH –Myristic acid
C15H31COOH-Palmitic acid
C9H19COOH- Decanoic acid
Unsaturated fatty acid
These are fatty acids which contain carbon-carbon double bonds. They have general formula
(CnH2n-1 COOH). They are subdivided into
Monounsaturated fatty acid: These are fatty acids containing one carbon-carbon double
bond. Oleic acid: is a C- 18 fatty acid with one double bond at position 9, is the most
abundant fatty acid in humans. CH3 (CH2)7CH = CH (CH2)7COOH
Polyunsaturated fatty acid: These are fatty acids that contain more than one carbon-carbon
double bond.

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Linoleic acid and Linolenic acid are polyunsaturated fatty acids called essential fatty acids
because they are required in the body and cannot be synthesized by human body. So they
need to be included in the diet.
5.2.2. Fats & Oils
Triacylglycerols, also called triglycerides, are compounds in which the three OH groups of
glycerol are esterified with fatty acids. If the three fatty acid components of a triacylglycerol
are the same, the compound is called a simple triacylglycerol. Mixed triacylglycerols, on the
other hand, contain two or three different fatty acid components and are more common than
simple triacylglycerols. Not all triacylglycerol molecules from a single source are necessarily
identical; substances such as lard and olive oil, for example, are mixtures of several different
triacylglycerols.

Triacylglycerols that are solids or semisolids at room temperature are called fats. Fats are
usually obtained from animals and are composed largely of triacylglycerol with either
saturated fatty acids or fatty acids with only one double bond.
5.2.3. Waxes
Waxes are esters formed from long-chain carboxylic acids and long-chain alcohols. For
example, beeswax, the structural material of beehives, has a 16-carbon carboxylic acid
component and a 30-carbon alcohol component. The word wax comes from the Old English
“weax”, meaning “material of the honeycomb”. Carnauba wax is a particularly hard wax
because of its relatively high molecular weight, arising from a32-carbon carboxylic acid
component and a 34-carbon alcohol component. Carnauba wax is widely used as a car wax
and in floor polishes.

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5.2.4 Phospholipids
Phosphoacylglycerols (also called phosphoglycerides) are the major components of cell
membranes. They are similar to triacylglycerols except that a terminal OH group of glycerol
is esterified with phosphoric acid rather than with a fatty acid, forming a Phosphatidic acid.
Because phosphoacylglycerols are lipids that contain a phosphate group, they are classified as
phospholipids. The C-2 carbon of glycerol in phosphoacylglycerols has the R configuration.

Phosphatidic acids are the simplest phosphoacylglycerols and are present only in small
amounts in membranes.
5.2.5 Prostaglandins
What are prostaglandins?
Prostaglandins are a group of lipids with hormone-like actions that your body makes
primarily at sites of tissue damage or infection. There are several different types of
prostaglandins, and they play several essential roles in regulating bodily processes, including:
Blood clot formation at the site of an injury.
Blood flow.
Healing.
Inflammation.
Labor induction in pregnancy.
Menstruation.
Ovulation.
Prostaglandins have a role in the natural physiology of your body in addition to their role in
defense and repair. For example, prostaglandins are responsible for uterine contractions

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during menstruation. These contractions help release the uterine lining (endometrium) from
your uterus, thus producing a period.
Healthcare providers also use synthetic forms of certain prostaglandins to treat various
conditions, including glaucoma and erectile dysfunction. They also use medications to block
certain prostaglandin receptors to help treat certain conditions.
Prostaglandin Structure
Prostaglandins are chemical messengers synthesized in the cells in which their physiological
activity is expressed. They are unsaturated fatty acids containing 20 carbon atoms and are
synthesized from arachidonic acid a polyunsaturated fatty acid when needed by a particular
cell. They are called prostaglandins because they were originally isolated from semen found
in the prostate gland. The unique shape of the arachidonic acid caused by a series of cis
double bonds helps to put it into position to make the five member ring of the prostaglandin.

Prostaglandins are one example of biologically important class of fatty acids called
eicosanoids. Derived primarily from arachidonic acid (5, 8, 11, 14-eicosatetraenoic acid),
eicosanoids include prostaglandins, leukotrienes, and thromboxane. It is now known that they
are synthesized in nearly all mammalian tissues and affect almost all organs in the body. The
five major classes of prostaglandins are designated as PGA, PGB, PGE, PGF, and PGI.
Subscripts are attached at the end of these abbreviations to denote the number of double
bonds outside the five-carbon ring in a given prostaglandin.
The metabolic pathways by which arachidonic acid is converted to the various prostaglandins
and eicosanoids are complex and will not be discussed here. A rough outline of some of the
transformations that take place is provided below. It is helpful to view Arachidonic acid in
the coiled conformation shown in the shaded box.

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Are prostaglandins hormones?

 Prostaglandins are lipids with hormone-like properties. Lipids are a class of organic
compounds that are fatty acids or their derivatives. Your body produces prostaglandins
from a fatty acid called arachidonic acid. Prostaglandins are hormone-like because they
coordinate different functions in your body and tell your body what to do and when to do
it.
 Prostaglandins are different from hormones because your endocrine system glands don’t
release them into your bloodstream like they do hormones. Instead, your tissues make
prostaglandins at the site of the action, damage or infection.
What is the function of prostaglandins?
There are several different types of prostaglandins and prostaglandin receptors that affect
almost every part of your body. The effect of prostaglandins depends on multiple factors,
including:
 The organ or tissue involved.
 The receptor to which they attach.
 The bodily function or physiological situation.
Prostaglandins can:
 Activate or inhibit (prevent) platelet build up for blood clot formation.
 Cause vasodilation (widening of blood vessels) or vasoconstriction (narrowing of
blood vessels).

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 Cause bronchoconstriction (the narrowing of air passageways) or bronchodilation

(widening of air passageways).
 Cause fever.
 Influence pain perception.
 Induce labor through uterine contractions.
 Cause your uterus to contract during menstruation to shed the uterine lining.
 Decrease pressure within your eye.
 Inhibit acid secretion in your stomach.
 Contract or relax smooth muscle in your gastrointestinal (GI) tract.
 Regulate several hormones.
Prostaglandins have a short half-life and have a short duration of action. Because of this, they
can only affect cells that are close by. Several different tissues throughout your body can
make prostaglandins. As an example, if you cut your finger, prostaglandins would play a part
in your body’s response in the following ways:
 The affected tissue in your finger would release prostaglandins that signal the platelets
in your blood to stick together to form a blood clot at the site of the injury in order to
stop the bleeding.
 The affected tissue would release prostaglandins to narrow affected blood vessels to
try to lessen blood loss.
 The affected tissue would release prostaglandins that trigger the inflammatory
response, causing blood vessels to leak fluid into the tissues (swelling). This helps
isolate any foreign substances that entered through your broken skin from further
contact with your body’s tissues. Prostaglandins involved with inflammation also
attract white blood cells called phagocytes that "eat" germs and dead or damaged
cells.
 Once your injury is healed, the affected tissue will release prostaglandins to break up
the blood clot and remove it since it’s no longer needed.
5.2.6 Terpenes
The name ‘terpene’ is derived from the Greek word ‘terebinth’. Terebinth is a type of pine
tree from which terpene-containing resins are obtained.
What are terpenes?
 They are natural organic compounds.

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 Components of a variety of fruit and floral flavors and aromas.

 Used in perfumes, essential oils and medicines.
Terpenes are unsaturated compounds formed by joining together isoprene units. They are
components of a wide variety of fruit and floral flavours and aromas. Terpene derivatives are
responsible for the distinctive aroma of spices.
The simpler mono and sesqui terpenes are chief constituent of the essential oils obtained from
sap and tissues of certain plants and trees. The di and tri terpenoids are not steam volatile.
They are obtained from plant and tree gums and resins. Tetra terpenoids form a separate
group of compounds called Carotenoids. The term 'terpene was originally employed to
describe a mixture of isomeric hydrocarbons of the molecular formula C 10H16 occurring in the
essential oils obtained from sap and tissue of plants, and-trees. But there is a tendency to use
more general term terpenoids which include hydrocarbons and their Oxygenated derivatives.
However the term terpene is being used these days by some authors to represent terpenoids.
By the modern definition: "Terperioids are the hydrocarbons of plant origin of the general
formula (C5H8)n as well as their oxygenated, hydrogenated and dehydrogenated derivatives”.
Isoprene rule: Thermal decomposition of terpenoids give isoprene as one of the product. Otto
Wallach pointed out that terpenoids can be built up of isoprene unit. Isoprene rule stats that
the terpenoid molecules are constructed from two or more isoprene unit.

Further Ingold suggested that isoprene units are joined in the terpenoid via ‘head to tail’
fashion. Special isoprene rule states that the terpenoid molecule is constructed of two or
more isoprene units joined in a ‘head to tail’ fashion.

But this rule can only be used as guiding principle and not as a fixed rule. For example
carotenoids are joined. Tail to tail at their central and there are also some terpenoids whose
carbon content is not a multiple of five. In applying isoprene rule we look only for the

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skeletal unit of carbon. The carbon skeletons of open chain mono terpenoids a
sesquiterpenoids are;

Classification of Terpenoids
 Most natural terpenoids hydrocarbon have the general formula (C 5H8) n. They can be
classified on the basis of value of n or number of carbon atoms present in the structure.
Each class can be further subdivided into subclasses according to the number of rings
present in the structure.
Acyclic terpenoids: they contain open structure.
Monocyclic terpenoids: they contain one ring in the structure.
Bicyclic terpenoids: they contain two rings in the structure.
Tricyclic terpenoids: they contain three rings in the structure.
Tetracyclic terpenoids: they contain four rings in the structure.
Classifications of terpenoids

General Properties of Terpenoids

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Most of the terpenoids are colourless, fragrant liquids which are lighter than water and
volatile with steam. A few of them are solids e.g. camphor. All are soluble in organic
solvent and usually insoluble in water. Most of them are optically active.
They are open chain or cyclic unsaturated compounds having one or more double
bonds. Consequently they undergo addition reaction with hydrogen, halogen, acids,
etc. A number of addition products have antiseptic properties.
They undergo polymerization and dehydrogenation.
They are easily oxidized nearly by all the oxidizing agents. On thermal
decomposition, most of the terpenoids yields isoprene as one of the product.
5.2.7. Steroids
Steroids are a man-made version of chemicals, known as hormones, which are made naturally
in the human body. Steroids are designed to act like these hormones to reduce inflammation.
They’re also known as corticosteroids, and are different to anabolic steroids used by
bodybuilders and athletes. Steroids won’t cure your condition, but they’re very good at
reducing inflammation and will ease symptoms such as swelling, pain and stiffness. Usually
inflammation is the body’s natural reaction to infection or bacteria. Your immune system
produces extra fluid to fight infections or bacteria, which causes swelling, redness and heat in
the affected area. You might have noticed this if you have had a cut or wound on your skin.
Steroids are compounds constituted of four fused rings, for example, the most common and
best known steroid in humans, cholesterol. In animals, steroids are biosynthesized from
lanosterol and are widely distributed. The distinctive feature in steroids is lack of methyl
group at C-4 position as compared to terpenes. In this section, we have classified steroids into
five basic categories based upon their chemical composition.

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Typical chemical structure of steroids

Steroid Hormones: Estranes, Androstanes, Pregnanes
Certain kinds of steroids like estrogenes, androstanes and pregnanes can act as hormones,
their activities being closely related to their structures (Table below). Pregnane-type steroids
can be classified into corticoids and progestogens based on their bioactivities. Their
classification and the typical compounds in each category are illustrated as follows:

Classification of steroid hormones

Estrogens: Estrogens function as the primary female sex hormone and in combination with
synthetic progestogens can be used as oral contraceptives to suppress ovulation. Recently, it
is also reported that they are effective for the prevention of osteoporosis, heart attacks and
Alzheimer’s disease in women.
Androgens: Testosterone is not only the principal and most well-known male sex hormone
but is also known to exert anabolic effects. This is also the main reason why some of them

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have been banned from use as bone density enhancers and muscle building drugs by several
sports organizations. They are also the intermediates of estrogene biosynthetic pathway or
rather the precursors of all estrogens.
Progestogens: The only naturally occurring progestogen, i.e., progesterone, exhibits anti
ovulatory action. Based on its structure, derivatives of 19-nortestosterone were synthesized
and can be used as oral contraceptives.
Corticoids: Synthetic corticoids such as dexamethasone and prednisolone find clinical use as
anti-inflammatory agents. They are synthetically developed based on the structure of
cortisone, a natural corticoid.
Warning: Some of the steroid hormones may cause serious physiological actions. To avoid
inhalation and contacting with skin, wear protective goggles, mask and eyeglasses when
handling. Sufficient caution should be taken, when using these compounds, from the opening
up to the disposal of the reagents.
Bile Acids: Cholanes
Cholane type steroids are predominantly found in the bile. Cholic acid and its derivatives
exist in bile as the major component as conjugates of glycine and taurine. Since conjugated
cholates are amphiphilic, they assist in the digestion and absorption of lipids in small
intestine. This characteristic is also exploited also in its use as a surfactant.
Cholesterol: Cholestanes
Cholesterol possesses a cholestane-type skeleton and in conjugation with fatty acids, it forms
the main component of cell membranes in animals and microorganisms. These cholesterol
conjugates establish and maintain proper membrane permeability. In addition, it is a
precursor of steroids as mentioned above and also exists in its liberated form in organisms.
Phytosteroids, Steroid Glycosides, Other Steroids
Steroids of plant origin have different biosynthetic pathways: they are synthesized from cyclo
artenol. They possess structural features distinct from animal steroids, for instance, a
characteristic alkyl side-chain at C-24.
5.3. Proteins and Amino Acids
5.3.1 α-Amino Acids
Amino acids are carboxylic acids that contain an amine functional group. Under certain
conditions the amine group of one molecule and carboxyl group a second can react, uniting

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the two amino acids by an amide bond. The general formula of an amino acid can be written
as,

An amino acid is an amino carboxylic acid. R is the side chain or residue and it represents the
group other than -NH2 and -COOH. It may be a hydrogen atom (H) or a methyl group (- CH 3)
or an aliphatic group or an aromatic group or a heterocyclic group.
All α-amino acids have trivial names, which usually reflect the property of that compound or
its source. Glycine is so named since it has sweet taste (in Greek glykos means sweet) and
tyrosine was first obtained from cheese (in Greek, tyros means cheese.) Amino acids are
generally represented by a three letter symbol, sometimes one letter symbol is also used.
The amino acids are classified based on the nature of their R groups, in particular their
polarity or tendency to interact with water at biological pH. The polarity of the R groups
varies widely, from totally non polar to highly polar.
a) Non-polar, aliphatic R-group
The R-group in this class of amino acids are non-polar (or) hydrophobic. Six amino acids
come under this class, which are glycine, alanine, valine, leucine, isoleucine and methionine.
Glycine has the simplest structure. Although it is formally nonpolar, it’s very small side chain
makes no real contribution to hydrophobic interactions. Methionine, one of the two sulfur-
containing amino acids, has a nonpolar thioether group in its side chain. Proline has an
aliphatic side chain with a distinctive cyclic structure. The secondary amino (imino) group of
proline residues is held in a rigid conformation that reduces the structural flexibility of
polypeptide regions containing proline.

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Non-polar, aliphatic R groups of common acids of proteins

b) Aromatic R groups
Two amino acids; phenylalanine and tyrosine contains benzene rings. As its name indicates,
phenylalanine is phenyl-substituted alanine. Tyrosine is phenylalanine with a para-hydroxy
substituent. Proline, histidine, and tryptophan are heterocyclic amino acids. Proline has its
nitrogen incorporated into a five-membered ring—it is the only amino acid that contains a
secondary amino group. Histidine is an imidazole-substituted alanine. Imidazole is an
aromatic compound because it is cyclic and planar and has three pairs of delocalized
electrons. The pKa value of a protonated imidazole ring is 6.0, so the ring will be protonated
in acidic solutions and non-protonated in basic solutions.
Phenylalanine, tyrosine and tryptophan, with their aromatic side chains, are relatively non-
polar (hydrophobic). All can participate in hydrophobic interactions. The hydroxyl group of
tyrosine can form hydrogen bond with other compounds and it is an important functional
group in some enzymes. Tyrosine and tryptophan are significantly more polar than phenyl
alanine because of the hydroxyl group of tyrosine and the nitrogen of the indole ring in
tryptophan.

Tryptophan is an indole-substituted alanine. Like imidazole, indole is an aromatic compound.

Because the lone pair on the nitrogen atom of indole is needed for the compound‘s
aromaticity, indole is a very weak base.
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Aromatic R groups of common amino acids of proteins

c) Polar-uncharged R groups
The R groups of these amino acids are more soluble in water or more hydrophilic, than those
of the non-polar amino acids because they contain functional groups that form hydrogen
bonds with water. This class of amino acids includes serine, threonine, cysteine, proline,
asparagine and glutamine. The polarity of serine and threonine is contributed by their
hydroxyl groups; that of cysteine by its sulphydryl (-SH) group; and that of asparagine and
glutamine by their amide groups. Proline has a distinct cyclic structure and is only
moderately polar. Proline has an imino group. Cysteine is readily oxidized to form a
covalently linked dimeric amino acid called cystine, in which two cysteine molecules are
joined by a disulphide bond.

Based on their inclusion in the diet, amino acids are classified into two groups, namely
essential amino acids and non-essential amino acids Amino Acids can be also classified as
essential and non-essential amino acids.
An essential amino acid or indispensable amino acid is an amino acid that cannot be
synthesized by the organism (usually referring to humans), and therefore must be supplied in

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the diet (meat, fish, fowl, eggs and dairy products).Ten amino acids are generally regarded as
essential for humans: phenylalanine, valine, threonine, tryptophan, isoleucine, methionine,
leucine, lysine, histidine and isoleucine.
The nonessential amino acids (can be synthesized by the organism or by our body) are
alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, proline, serine
and taurine.
5.3.2 Reactions of Amino Acids
Amino acids undergo reactions characteristic of both their amine and carboxylic acid
functional groups. Acylation is a typical reaction of the amino group.

Ester formation is a typical reaction of the carboxyl group.

Some Biochemical Reactions of Amino Acids

L-Glutamic acid is none essential amino acid. It need not be present in the diet, since animals
can biosynthesize it from sources of α-ketoglutaric acid. It is, however, a key intermediate in
the biosynthesis of other amino acids by a process known as transamination. Example: L-
Alanine

Mechanism of transamination.
All the steps are enzyme-catalyzed.
Step 1: The amine function of L-glutamate reacts with the ketone carbonyl of pyruvate to
form an imine.

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Step 2: Enzyme-catalyzed proton-transfer steps cause migration of the double bond,

converting the imine formed in step 1 to an isomeric imine.

Step 3: Hydrolysis of the rearranged imine gives L-alanine and α-ketoglutarate.

5.3.4 Peptides & Proteins

Peptides (from the Greek word means "digested") are short polymers of amino acid
(monomers) linked by peptide bonds, the covalent chemical bonds formed between two
molecules when the carboxyl group of one molecule reacts with the amino group of the other
molecule. Peptides are distinguished from proteins on the basis of size, typically containing
fewer than 50 amino acid units.
The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide
bond. There are also tripeptides, tetrpeptides, etc. Amino acids which have been incorporated
into a peptide are termed "residues"; every peptide has a N-terminus and C-terminus residue
on the ends of the peptide. A polypeptide is a long, continuous, and unbranched peptide.
Proteins consist of one or more polypeptides arranged in a biologically functional way and
are often bound to cofactors, or other proteins. Long peptides such as amyloid beta can be
considered proteins, whereas small proteins such as insulin can be considered peptides.
Proteins are the most abundant biomolecules of the living system. Chief sources of proteins
are milk, cheese, pulses, peanuts, fish, meat, etc. They occur in every part of the body and
form the fundamental basis of structure and functions of life. They are also required for
growth and maintenance of body. The word protein is derived from Greek word, “proteios”
which means primary or of prime importance. All proteins are polymers of α-amino acids.
Proteins are naturally occurring polypeptides that are made up of 40 to 4000 amino acid
residues. Amino acids are classified as, α, β, γ, and so on, according to the location of amine

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group on carbon chain that contains the carboxylic acids functional group. All organisms use
the same 20 amino acids as building blocks for the assembly of protein molecules. These 20
amino acids are called the common, or standard, amino acids.
Peptide bond formation
Amino acids are linked together by condensation reaction between carboxylic and amino
groups from two different amino acids (with elimination of water). The amide bond formed is
called peptide bond. The product is called a peptide, and named according to the number of
amino acids involved: e.g. dipeptide (2 AA), tripeptide (3 AA), decapeptide (10 AA) and so
on. Big peptides (> 50 amino acids) are called polypeptides.
Peptides and proteins are polymers of amino acids linked together by amide bonds. The
repeating units are called amino acid residues.

Protein Structure
There are four Levels of protein structure.
A. Primary structure describes the linear sequence of amino acid residues in a protein.
Recall that amino acid sequences are always written from the amino terminus (N-
terminus) to the carboxyl terminus (C-terminus). The three-dimensional structure of a
protein is described by three additional levels: secondary structure, tertiary structure,
and quaternary structure. The forces responsible for maintaining, or stabilizing, these
three levels are primarily noncovalent.

The linear sequence of amino acid residues defines the primary structure.
B. Secondary structure refers to regularities in local conformations, maintained by
hydrogen bonds between amide hydrogens and carbonyl oxygens of the peptide
backbone. The major secondary structures are α-helices and β-strands (including β-
sheets). Cartoons showing the structures of folded proteins usually represent α-helical

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regions by helices, and β strands by broad arrows pointing in the N-terminal to C-

terminal direction.

Secondary structure consists of regions of regularly repeating conformations of the peptide

chain, such as α-helices and β-sheets.
C. Tertiary structure describes the completely folded and compacted polypeptide
chain. Many folded polypeptides consist of several distinct globular units linked by a
short stretch of amino acid residues. Such units are called domains. Tertiary
structures are stabilized by the interactions of amino acid side chains in non-
neighboring regions of the polypeptide chain. The formation of tertiary structure
brings distant portions of the primary and secondary structures close together.

Tertiary structure describes the shape of the fully folded polypeptide chain. The example
shown has two domains.
D. Quaternary structure, some proteins possess which involves the association of two
or more polypeptide chains into a multisubunit, or oligomeric, protein. The
polypeptide chains of an oligomeric protein may be identical or different.

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Quaternary structure refers to the arrangement of two or more polypeptide chains into a
multisubunit molecule.
Denaturation of Proteins
Denaturation may be defined as a disruption of the secondary, tertiary, and wherever
applicable quaternary organization of a protein molecule due to cleavage of noncovalent
bonds. Agents that cause denaturation.
The following are some of the ways that proteins can be denatured:
 Changing the pH denatures proteins because it changes the charges on many of the
side chains. This disrupts electrostatic attractions and hydrogen bonds.
 Certain reagents such as urea and guanidine hydrochloride denature proteins by
forming hydrogen bonds to the protein groups that are stronger than the hydrogen
bonds formed between the groups.
 Detergents such as sodium dodecyl sulfate denature proteins by associating with the
nonpolar groups of the protein, thus interfering with the normal hydrophobic
interactions.
 Organic solvents denature proteins by disrupting hydrophobic interactions.
 Proteins can also be denatured by heat or by agitation. Both increase molecular
motion, which can disrupt the attractive forces. A well-known example is the change
that occurs to the white of an egg when it is heated or whipped.
5.3.7 Peptide Synthesis
Peptide synthesis is characterized as the formation of a peptide bond between two amino
acids. While there is no definitive definition of a peptide, it usually refers to flexible (little
secondary structure) chains of up to 30-50 amino acids. The importance of peptide synthesis
strategies besides having the ability to make peptides that are found in biological specimens,
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creativity and imagination can be tapped to generate unique peptides to optimize a desired
biological response or other result.
Peptide synthesis most often occurs by coupling the carboxyl group of the incoming amino
acid to the N-terminus of the growing peptide chain. This C-to-N synthesis is opposite from
protein biosynthesis, during which the N-terminus of the incoming amino acid is linked to the
C-terminus of the protein chain (N-to-C). Due to the complex nature of in vitro protein
synthesis, the addition of amino acids to the growing peptide chain occurs in a precise, step-
wise and cyclic manner. And while the common methods of peptide synthesis have some
critical differences, they all follow the same step-wise method to add amino acids one-at-a-
time to the growing peptide chain.
Because amino acids have multiple reactive groups, peptide synthesis must be carefully
performed to avoid side reactions that can reduce the length and cause branching of the
peptide chain. To facilitate peptide formation with minimal side reactions, chemical groups
have been developed that bind to the amino acid reactive groups and block, or protect, the
functional group from nonspecific reaction.

Scheme: peptide synthesis. The N-terminal protecting group on the C-terminal amino acid
of the peptide to be synthesized is first deprotected. After removing the unbound protecting
groups, the next amino acid is activated at the C-terminal end by a coupling agent, which
facilitates peptide bond formation between the deprotected N-terminus of the first amino acid
and the activated C-terminus of the incoming amino acid. The new N-terminus of the
growing peptide is then deprotected and coupled to the next amino acid. This cycle of
deprotection and coupling is repeated until the full-length peptide is formed.

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5.4 Nucleic Acids

5.4.1 Introduction to the chemistry of Nucleic Acids (Structure and Chemistry)
Nucleic acids are biological macromolecules that involved in the transfer of genetic
information and the control of protein biosynthesis. As their name implies, they are acidic
substances present in the nuclei of cells. There are two major kinds of nucleic acids:
ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). To understand the complex
structure of nucleic acids, we first need to examine some simpler substances, nitrogen
containing aromatic heterocycles called pyrimidines and purines.

The pyrimidines that occur in DNA are cytosine and thymine. Cytosine is also a structural
unit in RNA, which, however, contains uracil instead of thymine. Other pyrimidine
derivatives are sometimes present but in small amounts.

Adenine and guanine are the principal purines of both DNA and RNA.

Nucleosides
The term nucleoside was once restricted to pyrimidine and purine N-glycosides of D-
ribofuranose and 2-deoxy-D-ribofuranose, because these are the substances present in nucleic
acids. Uridine is a representative pyrimidine nucleoside; it bears a D-ribofuranose group at N-
1. Adenosine is a representative purine nucleoside; its carbohydrate unit is attached at N-9.
(Base + sugar).

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It is customary to refer to the non-carbohydrate portion of a nucleoside as a purine or

pyrimidine base.
Nucleotides
Nucleotides are phosphoric acid esters of nucleosides. The 5‘-monophosphate of adenosine is
called 5‘-adenylic acid or adenosine 5‘-monophosphate (AMP) i.e. base +sugar + phosphate.

As its name implies, 5‘-adenylic acid is an acidic substance; it is a diprotic acid with pKa‘s
for ionization of 3.8 and 6.2, respectively. In aqueous solution at pH 7, both OH groups of the
P (O) (OH) 2 unit are ionized. The analogous D-ribonucleotides of the other purines and
pyrimidines are uridylic acid,guanylic acid, and cytidylic acid. Thymidylic acid is the 5‘-
monophosphate of thymidine (the carbohydrate is 2-deoxyribose in this case). Other
important 5‘-nucleotides of adenosine include adenosine diphosphate (ADP) and
adenosinetriphosphate (ATP):

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Each phosphorylation step in the sequence shown is endothermic:

Nucleic Acids
Nucleic acids are polynucleotide’s in which a phosphate ester unit links the 5‘oxygen of one
nucleotide to the 3‘oxygen of another. Nucleic acids are classified as ribonucleic acids (RNA)
or deoxyribonucleic acids (DNA) depending on the carbohydrate present. The genetic
information of an organism resides in the chromosomes present in each of its cells and that
individual chromosomes are made up of smaller units called genes. Genes are DNA, interest
in nucleic acids intensified. DNA exists as a double stranded pair of helices in which
hydrogen bonds are responsible for complementary base pairing between adenine (A) and
thymine (T), and between guanine (G) and cytosine (C).

Structure and replication of DNA: the double helix

Chargaff found that there was a consistent pattern in the composition of DNAs from various
sources. Although there was wide variation in the distribution of the bases among species,

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half the bases in all samples of DNA were purines and the other half were pyrimidines.
Furthermore, the ratio of the purine adenine (A) to the pyrimidine thymine (T) was always
close to 1:1. Likewise, the ratio of the purine guanine (G) to the pyrimidine cytosine (C) was
also close to 1:[Link] of human DNA, for example, revealed it to have the following
composition:

Feeling that the constancy in the A/T and G/C ratios was no accident, Watson and Crick
proposed that it resulted from a structural complementarity between A and T and between G
and C.
The Watson–Crick base pairing model for DNA structure holds the key to understanding the
process of DNA replication. During cell division a cell‘s DNA is duplicated, that in the new
cell being identical with that in the original cell. At one stage of cell division the DNA double
helix begins to unwind, separating the two chains.
Each strand serves as the template on which a new DNA strand is constructed. Each new
strand is exactly like the original partner because the A---T, G---C base pairing requirement
ensures that the new strand is the precise complement of the template, just as the old strand
was. As the double helix unravels, each strand becomes one half of a new and identical DNA
double helix.
DNA-directed protein biosynthesis
Protein biosynthesis is directed by DNA through the agency of several types of ribonucleic
acid called messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA).
There are two main stages in protein biosynthesis: transcription and translation. In the
transcription stage a molecule of mRNA having a nucleotide sequence complementary to one
of the strands of a DNA double helix is constructed.
Transcription begins at the 5‘end of the DNA molecule, and ribonucleotides with bases
complementary to the DNA bases are polymerized with the aid of the enzyme RNA
polymerase. Thymine does not occur in RNA; the base that pairs with adenine in RNA is
uracil. Unlike DNA, RNA is single-stranded

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